Activatable cytokine polypeptides and methods of use thereof

ABSTRACT

The disclosure features fusion proteins that are conditionally active variants of a cytokine of interest. In one aspect, the full-length polypeptides of the invention have reduced or minimal cytokine-receptor activating activity even though they contain a functional cytokine polypeptide. Upon activation, e.g., by cleavage of a linker that joins a blocking moiety, e.g. a steric blocking polypeptide, in sequence to the active cytokine, the cytokine can bind its receptor and effect signaling. Typically, the fusion proteins further comprise an in vivo half-life extension element, which may be cleaved from the cytokine in the tumor microenvironment.

RELATED APPLICATIONS

This application is a continuation-in-part of PCT/US2019/032320, filedon May 14, 2019, which claims the benefit of U.S. ProvisionalApplication 62/671,225, filed on May 14, 2018, U.S. ProvisionalApplication No. 62/756,504, filed on Nov. 6, 2018, U.S. ProvisionalApplication No. 62/756,507, filed on Nov. 6, 2018, and U.S. ProvisionalApplication No. 62/756,515, filed on Nov. 6, 2018; and claims thebenefit of U.S. Provisional Application No. 62/935,605, filed on Nov.14, 2019, each of which are incorporated herein by reference.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Sep. 22, 2020, isnamed 761146_000143_SL.txt and is 1,972,103 bytes in size.

BACKGROUND

The development of mature immunocompetent lymphoid cells fromless-committed precursors, their subsequent antigen-driven immuneresponses, and the suppression of these and unwanted autoreactiveresponses are highly dependent and regulated by cytokines (includinginterleukin-2 [IL-2], IL-4, IL-7, IL-9, IL-15, and IL-21) that utilizereceptors in the common y-chain (γc) family (Rochman et al., 2009) andfamily members including IL-12, 18 and 23. IL-2 is essential for thymicdevelopment of Treg cells and critically regulates several key aspectsof mature peripheral Treg and antigen-activated conventional T cells.Because of its potent T cell growth factor activity in vitro, IL-2 hasbeen extensively studied in part because this activity offered apotential means to directly boost immunity, e.g., in cancer and AIDS-HIVpatients, or a target to antagonize unwanted responses, e.g.,transplantation rejection and autoimmune diseases. Although in vitrostudies with IL-2 provided a strong rationale for these studies, thefunction of IL-2 in vivo is clearly much more complex as firstillustrated in IL-2-deficient mice, where a rapid lethal autoimmunesyndrome, not lack of immunity, was observed (Sadlack et al., 1993,1995). Similar observations were later made when the gene encodingIL-2Rα (Il2ra) and IL-2Rβ (Il2rb) were individually ablated (Suzuki etal., 1995; Willerford et al., 1995).

The present invention refers to conditionally active and/or targetedcytokines for use in the treatment of cancer and other diseasesdependent on immune up or down regulation. For example, the antitumoralactivity of some cytokines is well known and described and somecytokines have already been used therapeutically in humans. Cytokinessuch as interleukin-2 (IL-2) and interferon α (IFNα) have shown positiveantitumoral activity in patients with different types of tumors, such askidney metastatic carcinoma, hairy cell leukemia, Kaposi sarcoma,melanoma, multiple myeloma, and the like. Other cytokines like IFNβ, theTumor Necrosis Factor (TNF) α, TNFβ, IL-1, 4, 6, 12, 15 and the CSFshave shown a certain antitumoral activity on some types of tumors andtherefore are the object of further studies.

SUMMARY

Provided herein are therapeutic proteins, nucleic acids that encode theproteins, and compositions and methods of using the proteins and nucleicacids for the treatment of a disease or disorder, such as proliferativedisease, a tumorous disease, an inflammatory disease, an immunologicaldisorder, an autoimmune disease, an infectious disease, a viral disease,an allergic reaction, a parasitic reaction, graft-versus-host diseaseand the like. In certain embodiments, the protein is one or more of,including any combinations, SEQ ID NOs.: 193-271 and the proteinreferred to herein as:

ACP200 ACP201 ACP202 ACP203 ACP204 ACP205 ACP206 ACP207 ACP208 ACP211ACP213 ACP214 ACP215 ACP240 ACP241 ACP242 ACP243 ACP244 ACP245 ACP247ACP284 ACP285 ACP286 ACP287 ACP288 ACP289 ACP290 ACP291 ACP292 ACP296ACP297 ACP298 ACP299 ACP300 ACP302 ACP303 ACP304 ACP305 ACP306 ACP309ACP310 ACP311 ACP312 ACP313 ACP314 ACP336 ACP337 ACP338 ACP339 ACP340ACP341 ACP342 ACP343 ACP344 ACP345 ACP346 ACP347 ACP348 ACP349 ACP350ACP351 ACP352 ACP353 ACP354 ACP355 ACP356 ACP357 ACP358 ACP359 ACP371ACP372 ACP373 ACP374 ACP375 ACP376 ACP377 ACP378 ACP379 ACP383 ACP384ACP385 ACP386 ACP387 ACP388 ACP389 ACP390 ACP391 ACP392 ACP393 ACP394ACP395 ACP396 ACP397 ACP398 ACP399 ACP400 ACP401 ACP402 ACP403 ACP404ACP405 ACP406 ACP407 ACP408 ACP409 ACP410 ACP411 ACP412 ACP413 ACP414ACP415 ACP416 ACP417 ACP418 ACP419 ACP420 ACP421 ACP422 ACP423 ACP424ACP425 ACP426 ACP427 ACP428 ACP429 ACP430 ACP431 ACP432 ACP433 ACP434ACP439 ACP440 ACP441 ACP442 ACP443 ACP444 ACP445 ACP446 ACP447 ACP451ACP452 ACP453 ACP454 ACP455 ACP456 ACP457 ACP458 ACP459 ACP460 ACP461ACP462 ACP463 ACP464 ACP465 ACP466 ACP467 ACP468 ACP469 ACP470 ACP471

The invention features fusion proteins that are conditionally activevariants of a cytokine of interest. In one aspect, the full-lengthpolypeptides of the invention have reduced or minimal cytokine-receptoractivating activity even though they contain a functional cytokinepolypeptide. Upon activation, e.g., by cleavage of a linker that joins ablocking moiety, e.g. a steric blocking polypeptide, in sequence to theactive cytokine, the cytokine, e.g., IL-2, IL-7, IL-12, IL-15, IL-18,IL-21, IL-23, IFNalpha, IFNbeta, IFNgamma, TNFalpha, lymphotoxin,TGF-beta1, TGFbeta2, TGFbeta3, GM-CSF, CXCL10, CCL19, CCL20, CCL21 orfunctional fragment or mutein of any of the foregoing, can bind itsreceptor and effect signaling. If desired, the full-length polypeptidescan include a blocking polypeptide moiety that also provides additionaladvantageous properties. For example, the full-length polypeptide cancontain a blocking polypeptide moiety that also extends the serumhalf-life and/or targets the full-length polypeptide to a desired siteof cytokine activity. Alternatively, the full-length fusion polypeptidescan contain a serum half-life extension element and/or targeting domainthat are distinct from the blocking polypeptide moiety. Preferably, thefusion protein contains at least one element or domain capable ofextending in vivo circulating half-life. Preferably, this element isremoved enzymatically in the desired body location (e.g. proteasecleavage in the tumor microenvironment), restoring pharmacokineticproperties to the payload molecule (e.g. IL2 or IFNa) substantiallysimilar to the naturally occurring payload molecule. The fusion proteinsmay be targeted to a desired cell or tissue. As described hereintargeting is accomplished through the action of a blocking polypeptidemoiety that also binds to a desired target, or through a targetingdomain. The domain that recognizes a target antigen on a preferredtarget (for example a tumor-specific antigen), may be attached to thecytokine via a cleavable or non-cleavable linker. If attached by anon-cleavable linker, the targeting domain may further aid in retainingthe cytokine in the tumor, and it may be considered a retention domain.The targeting domain does not necessarily need to be directly linked tothe payload molecule, and it may be linked directly to another elementof the fusion protein. This is especially true if the targeting domainis attached via a cleavable linker.

In one aspect is provided a fusion polypeptide comprising a cytokinepolypeptide, or functional fragment or mutein thereof, and a blockingmoiety, e.g. a steric blocking domain. The blocking moiety is fused tothe cytokine polypeptide, directly or through a linker, and can beseparated from the cytokine polypeptide by cleavage (e.g, proteasemediated cleavage) of the fusion polypeptide at or near the fusion siteor linker or in the blocking moiety. For example, when the cytokinepolypeptide is fused to a blocking moiety through a linker that containsa protease cleavage site, the cytokine polypeptide is released from theblocking moiety and can bind its receptor, upon protease mediatedcleavage of the linker. The linker is designed to be cleaved at the siteof desired cytokine activity, for example in the tumor microenvironment,avoiding off-target cytokine activity and reducing overall toxicity ofcytokine therapy.

The blocking moiety can also function as a serum half-life extensionelement. In some embodiments, the fusion polypeptide further comprises aseparate serum half-life extension element. In some embodiments, thefusion polypeptide further comprises a targeting domain. In variousembodiments, the serum half-life extension element is a water-solublepolypeptide such as optionally branched or multi-armed polyethyleneglycol (PEG), full length human serum albumin (HSA) or a fragment thatpreserves binding to FcRn, an Fc fragment, or a nanobody that binds toFcRn directly or to human serum albumin.

In addition to serum half-life extension elements, the pharmaceuticalcompositions described herein preferably comprise at least one, or moretargeting domains that bind to one or more target antigens or one ormore regions on a single target antigen. It is contemplated herein thata polypeptide construct of the invention is cleaved, for example, in adisease-specific microenvironment or in the blood of a subject at theprotease cleavage site and that the targeting domain(s) will bind to atarget antigen on a target cell. At least one target antigen is involvedin and/or associated with a disease, disorder or condition. Exemplarytarget antigens include those associated with a proliferative disease, atumorous disease, an inflammatory disease, an immunological disorder, anautoimmune disease, an infectious disease, a viral disease, an allergicreaction, a parasitic reaction, a graft-versus-host disease or ahost-versus-graft disease.

In some embodiments, a target antigen is a cell surface molecule such asa protein, lipid or polysaccharide. In some embodiments, a targetantigen is a on a tumor cell, virally infected cell, bacteriallyinfected cell, damaged red blood cell, arterial plaque cell, or fibrotictissue cell.

Target antigens, in some cases, are expressed on the surface of adiseased cell or tissue, for example a tumor or a cancer cell. Targetantigens for tumors include but are not limited to Fibroblast activationprotein alpha (FAPa), Trophoblast glycoprotein (5T4), Tumor-associatedcalcium signal transducer 2 (Trop2), Fibronectin EDB (EDB-FN),fibronectin EIIIB domain, CGS-2, EpCAM, EGFR, HER-2, HER-3, c-Met,FOLR1, FAP, and CEA. Pharmaceutical compositions disclosed herein, alsoinclude proteins comprising two antigen binding domains that bind to twodifferent target antigens known to be expressed on a diseased cell ortissue. Exemplary pairs of antigen binding domains include but are notlimited to EGFR/CEA, EpCAM/CEA, and HER-2/HER-3.

In some embodiments, the targeting polypeptides independently comprise ascFv, a VH domain, a VL domain, a non-Ig domain, or a ligand thatspecifically binds to the target antigen. In some embodiments, thetargeting polypeptides specifically bind to a cell surface molecule. Insome embodiments, the targeting polypeptides specifically bind to atumor antigen. In some embodiments, the targeting polypeptidesspecifically and independently bind to a tumor antigen selected from atleast one of EpCAM, EGFR, HER-2, HER-3, cMet, CEA, and FOLR1. In someembodiments, the targeting polypeptides specifically and independentlybind to two different antigens, wherein at least one of the antigens isa tumor antigen selected from EpCAM, EGFR, HER-2, HER-3, cMet, CEA, andFOLR1. In some embodiments, the targeting polypeptide serves as aretention domain and is attached to the cytokine via a non-cleavablelinker.

As described herein, the cytokine blocking moiety can bind to thecytokine and thereby block activation of the cognate receptor of thecytokine.

This disclosure also related to nucleic acids, e.g., DNA, RNA, mRNA,that encode the conditionally active proteins described herein, as wellas vectors and host cells that contain such nucleic acids.

This disclosure also relates to pharmaceutical compositions that containa conditionally active protein, nucleic acid that encodes theconditionally active protein, and vectors and host cells that containsuch nucleic acids. Typically, the pharmaceutical composition containsone or more physiologically acceptable carriers and/or excipients.

The disclosure also relates to therapeutic methods that includeadministering to a subject in need thereof an effective amount of aconditionally active protein, nucleic acid that encodes theconditionally active protein, vector or host cells that contain such anucleic acid, and pharmaceutical compositions of any of the foregoing.Typically, the subject has, or is at risk of developing, a proliferativedisease, a tumorous disease, an inflammatory disease, an immunologicaldisorder, an autoimmune disease, an infectious disease, a viral disease,an allergic reaction, a parasitic reaction, a graft-versus-host diseaseor a host-versus-graft disease.

The disclosure also relates to the use of a conditionally activeprotein, nucleic acid that encodes the conditionally active protein,vector or host cells that contain such a nucleic acid, andpharmaceutical compositions of any of the foregoing, for treating asubject in need thereof. Typically the subject has, or is at risk ofdeveloping, a proliferative disease, a tumorous disease, an inflammatorydisease, an immunological disorder, an autoimmune disease, an infectiousdisease, a viral disease, an allergic reaction, a parasitic reaction, agraft-versus-host disease or a host-versus-graft disease.

The disclosure also relates to the use of a conditionally activeprotein, nucleic acid that encodes the conditionally active protein,vector or host cells that contain such a nucleic acid for themanufacture of a medicament for treating a disease, such as aproliferative disease, a tumorous disease, an inflammatory disease, animmunological disorder, an autoimmune disease, an infectious disease, aviral disease, an allergic reaction, a parasitic reaction, agraft-versus-host disease or a host-versus-graft disease.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic illustrating a protease-activated cytokine orchemokine that includes a blocking moiety. The blocking moiety mayoptionally function as a serum half-life extending domain. To the leftof the arrow the drawing shows that a cytokine is connected to ablocking moiety via a protease-cleavable linker, thus blocking itsability to bind to its receptor. To the right of the arrow the drawingshows that in an inflammatory or tumor environment a protease cleaves ata protease-cleavage site on the linker, releasing the blocking moietyand allowing the cytokine to bind to its receptor.

FIG. 1B is a schematic illustrating a protease-activated cytokine orchemokine wherein HSA (blocking moiety) is directly bound to thecytokine or chemokine of interest, with a protease cleavage site betweenthe HSA and a cytokine or chemokine of interest. To the left of thearrow the drawing shows that a cytokine is connected to a blockingmoiety via a protease-cleavable linker, thus blocking its ability tobind to its receptor. To the right of the arrow the drawing shows thatin an inflammatory or tumor environment, the protease cleaves at aprotease-cleavage site on linker, releasing the blocking moiety andallowing the cytokine to bind to its receptor.

FIG. 1C is a schematic illustrating a protease-activated cytokine orchemokine wherein more than one HSA (blocking moiety) is bound directlyto the molecule of interest. If desired, one or more of the HSA can bebonded to the cytokine or chemokine through a linker, such as a linkerthat contains a protease cleavage site. To the left of the arrow thedrawing shows that a cytokine is connected to a blocking moiety via aprotease-cleavable linker, thus blocking its ability to bind to itsreceptor. To the right of the arrow the drawing shows that in aninflammatory or tumor environment, protease cleaves at protease-cleavagesite on linker, releasing the blocking moiety and allowing cytokine tobind receptor. The cytokine now has similar pK properties as compared tothe native cytokine (e.g., has a short half-life).

FIG. 1D is a schematic illustrating a protease-activated cytokine orchemokine comprising more than one cytokine, of the same type ordifferent type, each of which is bonded to a binding domain through aprotease-cleavable linker. To the left of the arrow the drawing showsthat a cytokine is connected to a blocking moiety via aprotease-cleavable linker, thus blocking its ability to bind to itsreceptor. To the right of the arrow the drawing shows that in aninflammatory or tumor environment a protease cleaves at a proteasecleavage site on linker, releasing the blocking moiety and allowing thecytokine to bind to its receptor.

FIG. 2 is a schematic illustrating a protease-activated cytokine orchemokine comprising a cytokine or chemokine polypeptide, a blockingmoiety, and a serum half-life extending domain connected by at least oneprotease-cleavable linker. To the left of the arrow the drawing showsthat a cytokine is connected to a blocking moiety via protease-cleavablelinkers, thus blocking its ability to bind to its receptor. It is alsobound to a separate half-life extension element, which extends half-lifein serum. To the right of the arrow the drawing shows that in aninflammatory or tumor environment a protease cleaves at aprotease-cleavage site on linker, thus releasing the serum half-lifeextension element and the blocking moiety and allowing the cytokine tobind to its receptor. The cytokine now has similar pK properties ascompared to the native cytokine (e.g., a short half-life).

FIG. 3 is a schematic illustrating a protease-activated cytokine orchemokine comprising a cytokine or chemokine polypeptide, a blockingmoiety, and a targeting domain connected by at least oneprotease-cleavable linker. To the left of the arrow the drawing showsthat a cytokine is connected to a blocking moiety and a targeting domainvia a protease-cleavable linker, thus blocking its ability to bind toits receptor. To the right of the arrow the drawing shows that in aninflammatory or tumor microenvironment a protease cleaves at theprotease cleavage site in the linker, releasing the targeting domain andthe blocking moiety and allowing the cytokine to bind to its receptor.

FIG. 4A is a schematic illustrating a protease-activated cytokine orchemokine comprising a cytokine or chemokine polypeptide, a blockingmoiety, a targeting domain, and a serum half-life extending domainconnected by at least one protease-cleavable linker, wherein thecytokine polypeptide and the targeting domain are connected by aprotease-cleavable linker. To the left of the arrow, the drawing showsthat a cytokine polypeptide is connected to targeting domain, blockingmoiety, and half-life extension element via protease-cleavablelinker(s), thus blocking its ability to bind to its receptor. To theright of the arrow the drawing shows that in an inflammatory or tumorenvironment, the protease cleaves at a protease-cleavage site onlinker(s), releasing the half-life extension element, the targetingdomain, and the blocking moiety, and allowing the cytokine to bind toits receptor. The cytokine now has similar pK properties as compared tothe native cytokine (e.g., short half-life).

FIG. 4B is a schematic illustrating a protease-activated cytokine orchemokine comprising a cytokine or chemokine polypeptide, a blockingmoiety, a targeting domain, and a serum half-life extending domainconnected by at least one protease-cleavable linker. To the left of thearrow, the drawing shows that a cytokine is connected to targetingdomain, a blocking moiety, and a half-life extension element viaprotease-cleavable linker(s), thus blocking its ability to bind to itsreceptor. To the right of the arrow the drawing shows that in aninflammatory or tumor environment, the protease cleaves at aprotease-cleavage site on linker(s), releasing the half-life extensionelement and the blocking moiety and allowing the cytokine to bind to thereceptor. The targeting moiety remains bound, keeping the cytokine inthe tumor microenvironment. The cytokine now has similar pK propertiesas compared to the native cytokine (e.g., a short half-life).

FIG. 5 is a schematic illustrating the structure of a variable domain ofan immunoglobulin molecule. The variable domains of both light and heavyimmunoglobulin chains contain three hypervariable loops, orcomplementarity-determining regions (CDRs). The three CDRs of a V domain(CDR1, CDR2, CDR3) cluster at one end of the beta barrel. The CDRs arethe loops that connect beta strands B-C, C′-C″, and F-G of theimmunoglobulin fold, whereas the bottom loops that connect beta strandsAB, CC′, C″-D and E-F of the immunoglobulin fold, and the top loop thatconnects the D-E strands of the immunoglobulin fold are the non-CDRloops.

FIG. 6. Place holder

FIGS. 7A-7H are a series of graphs showing activity of exemplary IL-2fusion proteins in IL-2 dependent cytotoxic T lymphocyte cell lineCTLL-2. Each graph shows results of the IL-2 proliferation assay asquantified by CellTiter-Glo® (Promega) luminescence-based cell viabilityassay. Each proliferation assay was performed with HSA (FIGS. 7B, 7D,7F, 7H) or without (FIGS. 7A, 7C, 7E, 7G). Each fusion protein comprisesan anti-HSA binder, and both uncleaved and MMP9 protease cleavedversions of the fusion protein were used in each assay.

FIGS. 8A-8F are a series of graphs showing activity of exemplary IL-2fusion proteins in IL-2 dependent cytotoxic T lymphocyte cell lineCTLL-2. Each graph shows results of the IL-2 proliferation assay asquantified by CellTiter-Glo (Promega) luminescence-based cell viabilityassay. Both uncleaved and MMP9 protease cleaved versions of the fusionprotein were used in each assay.

FIGS. 9A-9Z are a series of graphs showing activity of exemplary IL-2fusion proteins in IL-2 dependent cytotoxic T lymphocyte cell lineCTLL-2. Each graph shows results of the IL-2 proliferation assay asquantified by CellTiter-Glo (Promega) luminescence-based cell viabilityassay. Both uncleaved and MMP9 protease cleaved versions of the fusionprotein were used in each assay.

FIG. 10 shows results of protein cleavage assay. Fusion protein ACP16was run on an SDS-PAGE gel in both cleaved and uncleaved form. As can beseen in the gel, cleavage was complete.

FIGS. 11A-11B are graphs depicting results from a HEK-Blue IL-12reporter assay performed on human p40/murine p35 IL12 fusion proteinsbefore and after protease cleavage. Constructs ACP35 (FIG. 11A) andACP34 (FIG. 11B) were tested. Analysis was performed based onquantification of Secreted Alkaline Phosphatase (SEAP) activity usingthe reagent QUANTI-Blue® (InvivoGen). Results confirm that IL12 proteinfusion proteins are active.

FIGS. 12A-12F show a series of graphs depicting the results of HEK-blueassay of four IL-12 fusion proteins, before and after cleavage by MMP9.Analysis was performed based on quantification of Secreted AlkalinePhosphatase (SEAP) activity using the reagent QUANTI-Blue (InvivoGen).The data show greater activity in the cleaved IL12 than in the fullfusion protein. Constructs tested were ACP06 (FIG. 12A), ACP07 (FIG.12C), ACP08 (FIG. 12B), ACP09 (FIG. 12D), ACP10 (FIG. 12E), ACP11 (FIG.12F).

FIG. 13 shows results of protein cleavage assay. Fusion protein ACP11was run on an SDS-PAGE gel in both cleaved and uncleaved form. As can beseen in the gel, cleavage was complete.

FIG. 14 is a schematic which depicts a non-limiting example of aninducible cytokine protein, wherein the construct is activated uponprotease cleavage of a linker attached between two subunits of thecytokine.

FIGS. 15A-15D are graphs depicting results from a HEK-Blue assayperformed on human p40/murine p35 IL12 fusion proteins before and afterprotease cleavage. Results confirm that IL12 protein fusion proteins areactive. Each proliferation assay was performed with HSA or without HSA.

FIGS. 16A-16F are a series of graphs showing activity of exemplary IFNγfusion proteins compared to activity of mouse IFNγ control using WEHI279 cell survival assay. Each assay was performed with medium containingHSA (+HSA) or not containing HSA (−HSA). Each fusion protein comprisesan anti-HSA binder, and both uncleaved and MMP9 protease cleavedversions of the fusion protein were used in each assay.

FIGS. 17A-17F are a series of graphs showing activity of exemplary IFNγfusion proteins compared to activity of mouse IFNγ control using B16reporter assay. Each assay was performed with medium containing HSA(+HSA) or not containing HSA (−HSA). Each fusion protein comprises ananti-HSA binder, and both uncleaved and MMP9 protease cleaved versionsof the fusion protein were used in each assay.

FIGS. 18A-18B show results of protein cleavage assay, as described inExample 2. Two constructs, ACP31 (IFN-α fusion protein; FIG. 18A) andACP55 (IFN-γ fusion protein; 18B), were run on an SDS-PAGE gel in bothcleaved and uncleaved form. As can be seen in the gel, cleavage wascomplete.

FIGS. 19A-19B are a series of graphs (FIGS. 19A and 19B) showingactivity of exemplary IFNγ fusion proteins before and after proteasecleavage using B16 reporter assay. Each assay was performed with culturemedium containing HSA, and each fusion protein comprises an anti-HSAbinder. Both uncleaved and MMP9 protease cleaved versions of the fusionprotein were used in each assay.

FIGS. 20A-20B are a series of graphs (FIG. 20A and FIG. 20B) showingactivity of exemplary IFNα fusion proteins before and after cleavageusing a B16 reporter assay. Each assay was performed with mediumcontaining HSA, and each fusion protein comprises an anti-HSA binder.Both uncleaved and MMP9 protease cleaved versions of the fusion proteinwere used in each assay.

FIGS. 21A-21D are a series of graphs depicting the results of tumorgrowth studies using the MC38 cell line. FIGS. 21A-C show the effect ofIFNγ and IFNγ fusion proteins on tumor growth when injectedintraperitoneally (IP) using different dosing levels and schedules(ug=micrograms, BID=twice daily, BIW=twice weekly, QW=weekly). FIG. 21Dshows the effect of intratumoral (IT) injection of IFNγ and IL-2 ontumor growth.

FIGS. 22A-22B are a series of graphs showing activity of exemplary IFNγfusion proteins (ACP51 (FIG. 22A), and ACP52 (FIG. 22B)) cleaved by MMP9protease compared to activity of uncleaved fusion proteins using B16reporter assay. Each fusion protein comprises an anti-HSA binder and atumor targeting domain.

FIGS. 23A-23B are a series of graphs showing activity of exemplary IFNγfusion proteins (ACP53 and ACP54) cleaved by MMP9 protease compared toactivity of uncleaved fusion proteins using B16 reporter assay. Eachfusion protein comprises IFNγ directly fused to albumin.

FIGS. 24A-24D are graphs depicting results from a HEK-Blue IL-2 reporterassay performed on IL-2 fusion proteins and recombinant human IL2 (RechIL-2). Analysis was performed based on quantification of SecretedAlkaline Phosphatase (SEAP) activity using the reagent QUANTI-Blue(InvivoGen). FIG. 24A shows results of IL-2 constructs ACP132 and ACP133 with and without albumin. FIG. 24B shows results of IL-2 constructACP16 cleaved and uncleaved. Results of a protein cleavage assay ofACP16 in cleaved and uncleaved forms is also depicted. FIG. 24C showsresults of IL-2 construct ACP153 in cleaved and uncleaved forms. Resultsof a protein cleavage assay are also depicted. FIG. 24D illustrates theresults from a HEK-Blue IL-2 assay using wild-type cytokine, intactfusion protein, and protease-cleaved fusion protein.

FIGS. 25A and 25B are two graphs showing analysis of ACP16 (FIG. 25A)and ACP124 (FIG. 25B) in a HEKBlue IL-2 reporter assay in the presenceof HSA. Circles depict the activity of the uncut polypeptide, squaresdepict activity of the cut polypeptide. FIG. 25C is a graph showingresults of a CTLL-2 proliferation assay. CTLL2 cells (ATCC) were platedin suspension at a concentration of 500,000 cells/well in culture mediawith or without 40 mg/ml human serum albumin (HSA) and stimulated with adilution series of activatable hIL2 for 72 hours at 37° C. and 5% CO₂.Activity of uncleaved and cleaved activatable ACP16 was tested. Cleavedactivatable hIL2 was generated by incubation with active MMP9. Cellactivity was assessed using a CellTiter-Glo (Promega) luminescence-basedcell viability assay. Circles depict intact fusion protein, and squaresdepict protease-cleaved fusion protein.

FIGS. 26A-26C are a series of graphs showing activity of fusion proteinsin an HEKBlue IL-12 reporter assay. FIG. 26A depicts IL-12/STAT4activation in a comparison of ACP11 (a human p40/murine p35 IL12 fusionprotein) to ACP04 (negative control). FIG. 26B is a graph showinganalysis of ACP91 (a chimeric IL-12 fusion protein). Squares depictactivity of the uncut ACP91 polypeptide, and triangles depict theactivity of the cut polypeptide (ACP91+MMP9). EC50 values for each areshown in the table. FIG. 26C is a graph showing analysis of ACP136 (achimeric IL-12 fusion protein). Squares depict activity of the uncutACP136 polypeptide, and triangles depict the activity of the cutpolypeptide (ACP136+MMP9). EC50 values for each are shown in the tableinsert.

FIGS. 27A-27F are a series of graphs showing that cleaved mouse IFNα1polypeptides ACP31 (FIG. 27A), ACP125 (FIG. 27B), ACP126 (FIG. 27C) areactive in an B16-Blue IFN-α/β reporter assay.

FIGS. 28A-28N are a series of graphs depicting the activity of ACP56(FIG. 28A), ACP57 (FIG. 28B) ACP58 (FIG. 28C), ACP59 (FIG. 28D), ACP60(FIG. 28E), ACP61+HSA (FIG. 28F), ACP30+HSA (FIG. 28G), ACP73 (FIG.28H), ACP70+HSA (FIG. 28I), ACP71 (FIG. 28J), ACP72 (FIG. 28K), ACP 73(FIG. 28L), ACP74 (FIG. 28M), and ACP75 (FIG. 28N) in a B16 IFNγreporter assay. Each fusion was tested for its activity when cut(squares) and uncut (circles).

FIGS. 29A-29B are two graphs showing results of analyzing ACP31 (mouseIFNα1 fusion protein) and ACP11 (a human p40/murine p35 IL12 fusionprotein) in a tumor xenograft model. FIG. 29A shows tumor volume overtime in mice treated with 33 μg ACP31 (circles), 110 μg ACP31(triangles), 330 μg ACP31 (diamonds), and as controls 1 μg murine wildtype IFNα1 (dashed line, squares) and 10 μg mIFNα1 (dashed line, smallcircles). Vehicle alone is indicated by large open circles. The datashow tumor volume decreasing over time in a dose-dependent manner inmice treated with ACP31. FIG. 29B shows tumor volume over time in micetreated with 17.5 μg ACP11 (squares), 175 μg ACP31 (triangles), 525 μgACP31 (circles), and as controls 2 μg ACP04 (dashed line, triangles) and10 μg ACP04 (dashed line, diamonds). Vehicle alone is indicated by largeopen circles. The data show tumor volume decreasing over time in adose-dependent manner in mice treated with both ACP11 and ACP04 (a humanp40/murine p35 IL12 fusion protein).

FIGS. 30A-30F are a series of spaghetti plots showing tumor volume overtime in a mouse xenograft tumor model in mice each treated with vehiclealone (FIG. 30A), 2 μg ACP04 (FIG. 30B), 10 μg ACP04 (FIG. 30C, 17.5 μgACP11 (FIG. 30D), 175 μg ACP11 (FIG. 30E), and 525 μg ACP11 (FIG. 30F).Each line represents a single mouse.

FIG. 31A-31C are three graphs showing results of analyzing ACP16 andACP124 in a tumor xenograft model. FIG. 31A shows tumor volume over timein mice treated with 4.4 μg ACP16 (squares), 17 μg ACP16 (triangles), 70μg ACP16 (downward triangles), 232 μg ACP16 (dark circles), and as acomparator 12 μg wild type IL-2 (dashed line, triangles) and 36 μg wildtype IL-2 (dashed line, diamonds. Vehicle alone is indicated by largeopen circles. The data show tumor volume decreasing over time in adose-dependent manner in mice treated with ACP16 at higherconcentrations. FIG. 31B shows tumor volume over time in mice treatedwith 17 μg ACP124 (squares), 70 μg ACP124 (triangles), 230 μg ACP124(downward triangles), and 700 μg ACP124. Vehicle alone is indicated bylarge open circles. FIG. 31C shows tumor volume over time in micetreated with 17 μg ACP16 (triangles), 70 μg ACP16 (circles), 232 μgACP16 (dark circles), and as a comparator 17 μg ACP124 (dashed line,triangles) 70 μg ACP124 (dashed line, diamonds), 230 μg ACP124 (dashedline, diamonds). Vehicle alone is indicated by dark downward triangles.The data show tumor volume decreasing over time in a dose-dependentmanner in mice treated with ACP16, but not ACP124.

FIG. 32A Place holder

FIGS. 32B-32C are a series of spaghetti plots showing activity of fusionproteins in an MC38 mouse xenograft model corresponding to the datashown in FIG. 31. Each line in the plots is a single mouse.

FIG. 33 is a graph showing tumor volume over time in a mouse xenograftmodel showing tumor growth in control mice (open circles) andAP16-treated mice (squares).

FIGS. 34A-34D are a series of survival plots showing survival of miceover time after treatment with cleavable fusion proteins. FIG. 34A showsdata for mice treated with vehicle alone (gray line), 17 μg ACP16 (darkline), and 17μg ACP124 (dashed line). FIG. 34B shows data for micetreated with vehicle alone (gray line), 70 μg ACP16 (dark line), and 70μg ACP124 (dashed line). FIG. 34C shows data for mice treated withvehicle alone (gray line), 232 μg ACP16 (dark line), and 230 μg ACP124(dashed line). FIG. 34D shows data for mice treated with vehicle alone(gray line), 232 μg ACP16 (dark line), and 700 μg ACP124 (dashed line).

FIG. 35 a series of spaghetti plots showing activity of fusion proteinsin an MC38 mouse xenograft model. All mouse groups were given four dosestotal except for the highest three doses of APC132, wherein fataltoxicity was detected after 1 week/2 doses. Shown are vehicle alone(top), 17, 55, 70, and 230 μg ACP16 (top full row), 9, 28, 36, and 119μg ACP132 (middle full row), and 13, 42, 54, and 177 μg ACP21 (bottomfull row). Each line in the plots represents an individual animal.

FIGS. 36-41 Place holder

FIGS. 42A-42E shows the results of B16 IFN reporter assays. Inducibleinterferon constructs of interest were tested before and after cleavage.The relevant wildtype IFN was tested as a control.

FIG. 43 shows binding data of ACP16, ACP10, ACP11

FIGS. 44A-44D depict the activity of cytokine fusion proteins constructsACP243, ACP244, ACP243, ACP244, and ACP247.

FIG. 45 shows a series of spider plots showing tumor volume over timeduring treatment with vehicle, IL-12, ACP11 or ACP10.

FIGS. 46A-46D, 47A-47D, 48A-48B, 49A-49I, 50A-50B and 51A-51C shows data(tumor volume and/or body weight) for mice treated with cytokine fusionproteins constructs.

FIGS. 52A-52N, 53A, 53B depict the activity of cytokine fusion proteinsconstructs.

FIG. 54A-54N shows the results of proliferation assays comparing cutprotein, uncut protein, and IL2 as a control.

FIGS. 55A-55N shows the results of HekBlue IL2 reporter assays comparingactivity of constructs with and without protease cleavage; IL-2 isincluded as a control.

FIGS. 56. 57A-57D, 58, 59A-59C, 59E-59Z and 59AA depict the activity ofcytokine fusion proteins constructs.

DETAILED DESCRIPTION

Disclosed herein are methods and compositions to engineer and useconstructs comprising inducible cytokines. Cytokines are potent immuneagonists, which lead to them being considered promising therapeuticagents for oncology. However, cytokines proved to have a very narrowtherapeutic window. Cytokines have short serum half-lives and are alsoconsidered to be highly potent. Consequently, therapeutic administrationof cytokines produced undesirable systemic effects and toxicities. Thesewere exacerbated by the need to administer large quantities of cytokinein order to achieve the desired levels of cytokine at the intended siteof cytokine action (e.g., a tumor). Unfortunately, due to the biology ofcytokines and inability to effectively target and control theiractivity, cytokines did not achieve the hoped-for clinical advantages inthe treatment of tumors.

Disclosed herein are fusion proteins that overcome the toxicity andshort half-life problems that have severely limited the clinical use ofcytokines in oncology. The fusion proteins contain cytokine polypeptidesthat have receptor agonist activity. But in the context of the fusionprotein, the cytokine receptor agonist activity is attenuated and thecirculating half-life is extended. The fusion proteins include proteasecleave sites, which are cleaved by proteases that are associated with adesired site of cytokine activity (e.g., a tumor), and are typicallyenriched or selectively present at the site of desired activity. Thus,the fusion proteins are preferentially (or selectively) and efficientlycleaved at the desired site of activity to limit cytokine activitysubstantially to the desired site of activity, such as the tumormicroenvironment. Protease cleavage at the desired site of activity,such as in a tumor microenvironment, releases a form of the cytokinefrom the fusion protein that is much more active as a cytokine receptoragonist than the fusion protein (typically at least about 100× moreactive than the fusion protein). The form of the cytokine that isreleased upon cleavage of the fusion protein typically has a shorthalf-life, which is often substantially similar to the half-life of thenaturally occurring cytokine, further restricting cytokine activity tothe tumor microenvironment. Even though the half-life of the fusionprotein is extended, toxicity is dramatically reduced or eliminatedbecause the circulating fusion protein is attenuated and active cytokineis targeted to the tumor microenvironment. The fusion proteins describedherein, for the first time, enable the administration of an effectivetherapeutic dose of a cytokine to treat tumors with the activity of thecytokine substantially limited to the tumor microenvironment, anddramatically reduces or eliminates unwanted systemic effects andtoxicity of the cytokine.

Unless otherwise defined, all terms of art, notations and otherscientific terminology used herein are intended to have the meaningscommonly understood by those of skill in the art to which this inventionpertains. In some cases, terms with commonly understood meanings aredefined herein for clarity and/or for ready reference, and the inclusionof such definitions herein should not necessarily be construed torepresent a difference over what is generally understood in the art. Thetechniques and procedures described or referenced herein are generallywell understood and commonly employed using conventional methodologiesby those skilled in the art, such as, for example, the widely utilizedmolecular cloning methodologies described in Sambrook et al., MolecularCloning: A Laboratory Manual 4th ed. (2012) Cold Spring HarborLaboratory Press, Cold Spring Harbor, N.Y. As appropriate, proceduresinvolving the use of commercially available kits and reagents aregenerally carried out in accordance with manufacturer-defined protocolsand conditions unless otherwise noted.

“Cytokine” is a well-known term of art that refers to any of a class ofimmunoregulatory proteins (such as interleukin or interferon) that aresecreted by cells especially of the immune system and that aremodulators of the immune system. Cytokine polypeptides that can be usedin the fusion proteins disclosed herein include, but are not limited totransforming growth factors, such as TGF-α and TGF-β (e.g., TGFbeta1,TGFbeta2, TGFbeta3); interferons, such as interferon-α, interferon-β,interferon-γ, interferon-kappa and interferon-omega; interleukins, suchas IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10,IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-21 and IL-25;tumor necrosis factors, such as tumor necrosis factor alpha andlymphotoxin; chemokines (e.g., C—X—C motif chemokine 10 (CXCL10), CCL19,CCL20, CCL21), and granulocyte macrophage-colony stimulating factor(GM-CS), as well as fragments of such polypeptides that active thecognate receptors for the cytokine (i.e., functional fragments of theforegoing). “Chemokine” is a term of art that refers to any of a familyof small cytokines with the ability to induce directed chemotaxis innearby responsive cells.

Cytokines are well-known to have short serum half-lives that frequentlyare only a few minutes or hours. Even forms of cytokines that havealtered amino acid sequences intended to extend the serum half-life yetretain receptor agonist activity typically also have short serumhalf-lives. As used herein, a “short-half-life cytokine” refers to acytokine that has a substantially brief half-life circulating in theserum of a subject, such as a serum half-life that is less than 10, lessthan 15, less than 30, less than 60, less than 90, less than 120, lessthan 240, or less than 480 minutes. As used herein, a short half-lifecytokine includes cytokines which have not been modified in theirsequence to achieve a longer than usual half-life in the body of asubject and polypeptides that have altered amino acid sequences intendedto extend the serum half-life yet retain receptor agonist activity. Thislatter case is not meant to include the addition of heterologous proteindomains, such as a bona fide half-life extension element, such as serumalbumin.

“Sortases” are transpeptidases that modify proteins by recognizing andcleaving a carboxyl-terminal sorting signal embedded in or terminallyattached to a target protein or peptide. Sortase A catalyzes thecleavage of the LPXTG motif (SEQ ID NO.: 442) (where X is any standardamino acid) between the Thr and Gly residue on the target protein, withtransient attachment of the Thr residue to the active site Cys residueon the enzyme, forming an enzyme-thioacyl intermediate. To completetranspeptidation and create the peptide-monomer conjugate, a biomoleculewith an N-terminal nucleophilic group, typically an oligoglycine motif,attacks the intermediate, displacing Sortase A and joining the twomolecules.

As used herein, the term “steric blocker” refers to a polypeptide orpolypeptide moiety that can be covalently bonded to a cytokinepolypeptide directly or indirectly through other moieties such aslinkers, for example in the form of a chimeric polypeptide (fusionprotein), but otherwise does not covalently bond to the cytokinepolypeptide. A steric blocker can non-covalently bond to the cytokinepolypeptide, for example though electrostatic, hydrophobic, ionic orhydrogen bonding. A steric blocker typically inhibits or blocks theactivity of the cytokine moiety due to its proximity to the cytokinemoiety and comparative size. A steric blocker may also block by virtueof recruitment of a large protein binding partner. An example of this isan antibody which binds to serum albumin; while the antibody itself mayor may not be large enough to block activation or binding on its own,recruitment of albumin allows for sufficient steric blocking.

As used and described herein, a “half-life extension element” is a partof the chimeric polypeptide that increases the serum half-life andimprove pK, for example, by altering its size (e.g., to be above thekidney filtration cutoff), shape, hydrodynamic radius, charge, orparameters of absorption, biodistribution, metabolism, and elimination.

As used herein, the terms “activatable,” “activate,” “induce,” and“inducible” refer to the ability of a protein, i.e. a cytokine, that ispart of a fusion protein, to bind its receptor and effectuate activityupon cleavage of additional elements from the fusion protein.

As used herein, “plasmids” or “viral vectors” are agents that transportthe disclosed nucleic acids into the cell without degradation andinclude a promoter yielding expression of the nucleic acid moleculeand/or polypeptide in the cells into which it is delivered.

As used herein, the terms “peptide”, “polypeptide”, or “protein” areused broadly to mean two or more amino acids linked by a peptide bond.Protein, peptide, and polypeptide are also used herein interchangeablyto refer to amino acid sequences. It should be recognized that the termpolypeptide is not used herein to suggest a particular size or number ofamino acids comprising the molecule and that a peptide of the inventioncan contain up to several amino acid residues or more.

As used throughout, “subject” can be a vertebrate, more specifically amammal (e.g. a human, horse, cat, dog, cow, pig, sheep, goat, mouse,rabbit, rat, and guinea pig), birds, reptiles, amphibians, fish, and anyother animal. The term does not denote a particular age or sex. Thus,adult and newborn subjects, whether male or female, are intended to becovered.

As used herein, “patient” or “subject” may be used interchangeably andcan refer to a subject with a disease or disorder (e.g. cancer). Theterm patient or subject includes human and veterinary subjects.

As used herein the terms “treatment”, “treat”, or “treating” refers to amethod of reducing the effects of a disease or condition or symptom ofthe disease or condition. Thus, in the disclosed method, treatment canrefer to at least about 10%, at least about 20%, at least about 30%, atleast about 40%, at least about 50%, at least about 60%, at least about70%, at least about 80%, at least about 90%, or substantially completereduction in the severity of an established disease or condition orsymptom of the disease or condition. For example, a method for treatinga disease is considered to be a treatment if there is a 10% reduction inone or more symptoms of the disease in a subject as compared to acontrol. Thus, the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90%, 100%, or any percent reduction in between 10% and 100% ascompared to native or control levels. It is understood that treatmentdoes not necessarily refer to a cure or complete ablation of thedisease, condition, or symptoms of the disease or condition.

As used herein, the terms “prevent”, “preventing”, and “prevention” of adisease or disorder refers to an action, for example, administration ofthe chimeric polypeptide or nucleic acid sequence encoding the chimericpolypeptide, that occurs before or at about the same time a subjectbegins to show one or more symptoms of the disease or disorder, whichinhibits or delays onset or exacerbation of one or more symptoms of thedisease or disorder.

As used herein, references to “decreasing”, “reducing”, or “inhibiting”include a change of at least about 10%, of at least about 20%, of atleast about 30%, of at least about 40%, of at least about 50%, of atleast about 60%, of at least about 70%, of at least about 80%, of atleast about 90% or greater as compared to a suitable control level. Suchterms can include but do not necessarily include complete elimination ofa function or property, such as agonist activity.

An “attenuated cytokine receptor agonist” is a cytokine receptor agonistthat has decreased receptor agonist activity as compared to the cytokinereceptor's naturally occurring agonist. An attenuated cytokine agonistmay have at least about 10×, at least about 50×, at least about 100×, atleast about 250×, at least about 500×, at least about 1000× or lessagonist activity as compared to the receptor's naturally occurringagonist. When a fusion protein that contains a cytokine polypeptide asdescribed herein is described as “attenuated” or having “attenuatedactivity”, it is meant that the fusion protein is an attenuated cytokinereceptor agonist.

An “intact fusion protein” is a fusion protein in which no domain hasbeen removed, for example by protease cleavage. A domain may beremovable by protease cleavage or other enzymatic activity, but when thefusion protein is “intact”, this has not occurred.

As used herein “moiety” refers to a portion of a molecule that has adistinct function within that molecule, and that function may beperformed by that moiety in the context of another molecule. A moietymay be a chemical entity with a particular function, or a portion of abiological molecule with a particular function. For example, a “blockingmoiety” within a fusion protein is a portion of the fusion protein whichis capable of blocking the activity of some or all of the fusionpolypeptide. This may be a protein domain, such as serum albumin.Blocking may be accomplished by a steric blocker or a specific blocker.A steric blocker blocks by virtue of size and position and not basedupon specific binding; an examples is serum albumin. A specific blockerblocks by virtue of specific interactions with the moiety to be blocked.A specific blocker must be tailored to the particular cytokine or activedomain; a steric blocker can be used regardless of the payload, as longas it is large enough.

In general, the therapeutic use of cytokines is strongly limited bytheir systemic toxicity. TNF, for example, was originally discovered forits capacity of inducing the hemorrhagic necrosis of some tumors, andfor its in vitro cytotoxic effect on different tumoral lines, but itsubsequently proved to have strong pro-inflammatory activity, which can,in case of overproduction conditions, dangerously affect the human body.As the systemic toxicity is a fundamental problem with the use ofpharmacologically active amounts of cytokines in humans, novelderivatives and therapeutic strategies are now under evaluation, aimedat reducing the toxic effects of this class of biological effectorswhile keeping their therapeutic efficacy.

IL-2 exerts both stimulatory and regulatory functions in the immunesystem and is, along with other members of the common γ chain (γc)cytokine family, central to immune homeostasis. IL-2 mediates its actionby binding to IL-2 receptors (IL-2R), consisting of either trimericreceptors made of IL-2Rα (CD25), IL-2Rβ (CD122), and IL-2Rγ (γc, CD132)chains or dimeric βγ IL-2Rs (1, 3). Both IL-2R variants are able totransmit signal upon IL-2 binding. However, trimeric αβγ IL-2Rs have aroughly 10-100 times higher affinity for IL-2 than dimeric βγ IL-2Rs(3), implicating that CD25 confers high-affinity binding of IL-2 to itsreceptor but is not crucial for signal transduction. Trimeric IL-2Rs arefound on activated T cells and CD4+ forkhead box P3 (FoxP3)+ Tregulatory cells (Treg), which are sensitive to IL-2 in vitro and invivo. Conversely, antigen-experienced (memory) CD8+, CD44 highmemory-phenotype (MP) CD8+, and natural killer (NK) cells are endowedwith high levels of dimeric βγ IL-2Rs, and these cells also respondvigorously to IL-2 in vitro and in vivo.

Expression of the high-affinity IL-2R is critical for endowing T cellsto respond to low concentrations of IL-2 that is transiently availablein vivo. IL-2Rα expression is absent on naive and memory T cells but isinduced after antigen activation. IL-2Rβ is constitutively expressed byNK, NKT, and memory CD8+ T cells but is also induced on naive T cellsafter antigen activation. γc is much less stringently regulated and isconstitutively expressed by all lymphoid cells. Once the high-affinityIL-2R is induced by antigen, IL-2R signaling upregulates the expressionof IL-2Rα in part through Stat5-dependent regulation of Il2ratranscription (Kim et al., 2001). This process represents a mechanism tomaintain expression of the high-affinity IL-2R and sustain IL-2signaling while there remains a source of IL-2.

IL-2 is captured by IL-2Rα through a large hydrophobic binding surfacesurrounded by a polar periphery that results in a relatively weakinteraction (Kd 10-8 M) with rapid on-off binding kinetics. However, theIL-2Rα-IL-2 binary complex leads to a very small conformational changein IL-2 that promotes association with IL-2Rβ through a distinct polarinteraction between IL-2 and IL-2Rβ. The pseudo-high affinity of theIL2/α/β trimeric complex (i.e. Kd˜300 pM) clearly indicates that thetrimeric complex is more stable than either IL2 bound to the a chainalone (Kd=10 nM) or to the β chain alone (Kd=450 nM) as shown byCiardelli's data. In any event, the IL2/α/β trimer then recruits the γchain into the quaternary complex capable of signaling, which isfacilitated by the large composite binding site on the IL2-bound β chainfor the γ chain.

In other words, the ternary IL-2Rα-IL-2Rβ-IL-2 complex then recruits γcthrough a weak interaction with IL-2 and a stronger interaction withIL-2Rβ to produce a stable quaternary high-affinity IL-2R (Kd 10-11 Mwhich is 10 pM). The formation of the high-affinity quaternaryIL-2-IL-2R complex leads to signal transduction through the tyrosinekinases Jak1 and Jak3, which are associated with IL-2Rβ and γc,respectively (Nelson and Willerford, 1998). The quaternary IL-2-IL-2Rcomplex is rapidly internalized, where IL-2, IL-2Rβ, and γc are rapidlydegraded, but IL-2Rα is recycled to the cell surface (Hamar et al.,1995; Yu and Malek, 2001). Thus, those functional activities thatrequire sustained IL-2R signaling require a continued source of IL-2 toengage IL-2Rα and form additional IL-2-IL-2R signaling complexes.

Interleukin-15 (IL-15), another member of the 4-alpha-helix bundlefamily of cytokines, has also emerged as an immunomodulator for thetreatment of cancer. IL-15 is initially captured via IL-15Rα, which isexpressed on antigen-presenting dendritic cells, monocytes andmacrophages. IL-15 exhibits broad activity and induces thedifferentiation and proliferation of T, B and natural killer (NK) cellsvia signaling through the IL-15/IL-2-R-β (CD122) and the common γ chain(CD132). It also enhances cytolytic activity of CD8⁺ T cells and induceslong-lasting antigen-experienced CD8⁺CD44 memory T cells. IL-15stimulates differentiation and immunoglobulin synthesis by B cells andinduces maturation of dendritic cells. It does not stimulateimmunosuppressive T regulatory cells (Tregs). Thus, boosting IL-15activity selectively in the tumor micro-environment could enhance innateand specific immunity and fight tumors (Waldmann et al., 2012). IL-15was initially identified for its ability to stimulate T cellproliferation in an IL-2-like manner through common receptor components(IL-2R/15Rβ-γc) and signaling through JAK1/JAK3 and STAT3/STATS. LikeIL-2, IL-15 has been shown to stimulate proliferation of activatedCD4-CD8−, CD4+CD8+, CD4+ and CD8+ T cells as well as facilitate theinduction of cytotoxic T-lymphocytes, and the generation, proliferationand activation of NK cells (Waldmann et al., 1999). However, unlike IL-2which is required to maintain forkhead box P3 (FOXP3)-expressingCD4+CD25+ Treg cells and for the retention of these cells in theperiphery, IL-15 has little effect on Tregs (Berger et al., 2009). Thisis important as FOXP3-expressing CD4+CD25+ Tregs inhibit effector Tcells, thereby inhibiting immune responses including those directedagainst the tumor. IL-2 also has a crucial role in initiating activationinduced cell death (AICD), a process that leads to the elimination ofself-reactive T cells, whereas IL-15 is an anti-apoptotic factor for Tcells (Marks-Konczalik et al., 2000). IL-15 co-delivered with HIVpeptide vaccines has been shown to overcome CD4+ T cell deficiency bypromoting longevity of antigen-specific CD8+ T cells and blockingTRAIL-mediated apoptosis (Oh et al., 2008). Furthermore, IL-15 promotesthe long-term maintenance of CD8+CD44hi memory T cells (Kanegane et al.,1996).

The importance of IL-15 and IL-15Rα to T and NK cell development isfurther highlighted by the phenotype of IL-15Rα^(−/−) and IL-15^(−/−)mice. Knockout mice demonstrate decreased numbers of total CD8+ cells,and are deficient in memory-phenotype CD8+ T cells, NK cells, NK/T cellsand some subsets of intestinal intraepithelial lymphocytes, indicatingthat IL-15 provides essential positive homeostatic functions for thesesubsets of cells (Lodolce et al., 1996; Kennedy et al., 1998). Thesimilarities in the phenotypes of these two strains of knockout micesuggest the importance of IL-15Rα in maintaining physiologicallyrelevant IL-15 signals.

IL-15 is presented in trans by the IL-15 receptor alpha-chain to theIL-15Rβγc complex displayed on the surface of T cells and natural killer(NK) cells (Han et al., 2011). The IL-15Ra-chain plays a role ofchaperone protein, stabilizes, and increases IL-15 activity (Desbois etal., 2016). It has been shown that exogenous IL-15 may have a limitedimpact on patients with cancer due to its dependency on IL-15Rafrequently downregulated in cancer patients. Therefore, the fusionprotein RLI, composed of the sushi+ domain of IL15Ra coupled via alinker to IL-15, has been suggested as an alternative approach to IL15therapy (Bessard et al., 2009). It was found that administration ofsoluble IL-15/IL-15Rα complexes greatly enhanced IL-15 serum half-lifeand bioavailability in vivo (Stoklasek et al., 2010).

In addition to the effects on T and NK cells, IL-15 also has severaleffects on other components of the immune system. IL-15 protectsneutrophils from apoptosis, modulates phagocytosis and stimulates thesecretion of IL-8 and IL-1R antagonist. It functions through theactivation of JAK2, p38 and ERK1/2 MAPK, Syk kinase and the NF-kBtranscriptional factor (Pelletier et al., 2002). In mast cells, IL-15can act as a growth factor and an inhibitor of apoptosis. In these cellsIL-15 activates the JAK2/STATS pathway without the requirement of γcbinding (Tagaya et al., 1996). IL-15 also induces B lymphocyteproliferation and differentiation, and increases immunoglobulinsecretion (Armitage et al., 1995). It also prevents Fas-mediatedapoptosis and allows induction of antibody responses partiallyindependent of CD4-help (Demerci et al., 2004; Steel et al., 2010).Monocytes, macrophages and dendritic cells effectively transcribe andtranslate IL-15. They also respond to IL-15 stimulation. Macrophagesrespond by increasing phagocytosis, inducing IL-8, IL-12 and MCP-1expression, and secreting IL-6, IL-8 and TNF α (Budagian et al., 2006).Dendritic cells incubated with IL-15 demonstrate maturation withincreased CD83, CD86, CD40, and MHC class II expression, are alsoresistant to apoptosis, and show enhanced interferon-γ secretion(Anguille et al., 2009). [97] IL-15 has also been shown to have effectson non-hematological cells including myocytes, adipocytes, endothelialand neural cells. IL-15 has an anabolic effect on muscle and may supportmuscle cell differentiation (Quinn et al., 1995). It stimulates myocytesand muscle fibers to accumulate contractile protein and is able to slowmuscle wasting in rats with cancer-related cachexia (Figueras et al.,2004). IL-15 has also been shown to stimulate angiogenesis (Angiolilloet al., 1997) and induce microglial growth and survival (Hanisch et al.,1997).

Interleukin-7 (IL-7), also of the IL-2/IL-15 family, is awell-characterized pleiotropic cytokine, and is expressed by stromalcells, epithelial cells, endothelial cells, fibroblasts, smooth musclecells and keratinocytes, and following activation, by dendritic cells(Alpdogan et al., 2005). Although it was originally described as agrowth and differentiation factor for precursor B lymphocytes,subsequent studies have shown that IL-7 is critically involved inT-lymphocyte development and differentiation. Interleukin-7 signaling isessential for optimal CD8 T-cell function, homeostasis and establishmentof memory (Schluns et al., 2000); it is required for the survival ofmost T-cell subsets, and its expression has been proposed to beimportant for regulating T-cell numbers.

IL-7 binds to a dimeric receptor, including IL-7Rα and γ_(c) to form aternary complex that plays fundamental roles in extracellular matrixremodeling, development, and homeostasis of T and B cells (Mazzucchelliand Durum, 2007). IL-7Rα also cross-reacts to form a ternary complexwith thymic stromal lymphopoietin (TSLP) and its receptor (TSLPR), andactivates the TSLP pathway, resulting in T and dendritic cellproliferation in humans and further B cell development in mice (Leonard,2002). Tight regulation of the signaling cascades activated by thecomplexes are therefore crucial to normal cellular function.Under-stimulation of the IL-7 pathway caused by mutations in the IL-7Rαectodomain inhibits T and B cell development, resulting in patients witha form of severe combined immunodeficiency (SCID) (Giliani et al., 2005;Puel et al., 1998).

IL-7 has a potential role in enhancing immune reconstitution in cancerpatients following cytotoxic chemotherapy. IL-7 therapy enhances immunereconstitution and can augment even limited thymic function byfacilitating peripheral expansion of even small numbers of recent thymicemigrants. Therefore, IL-7 therapy could potentially repair the immunesystem of patients who have been depleted by cytotoxic chemotherapy(Capitini et al., 2010).

Interleukin-12 (IL-12) is a disulfide-linked heterodimer of twoseparately encoded subunits (p35 and p40), which are linked covalentlyto give rise to the so-called bioactive heterodimeric (p70) molecule(Lieschke et al., 1997; Jana et al., 2014). Apart from formingheterodimers (IL-12 and IL-23), the p40 subunit is also secreted as amonomer (p40) and a homodimer (p40₂). It is known in the art thatsynthesis of the heterodimer as a single chain with a linker connectingthe p35 to the p40 subunit preserves the full biological activity of theheterodimer. IL-12 plays a critical role in the early inflammatoryresponse to infection and in the generation of Th1 cells, which favorcell-mediated immunity. It has been found that overproduction of IL-12can be dangerous to the host because it is involved in the pathogenesisof a number of autoimmune inflammatory diseases (e.g. MS, arthritis,type 1 diabetes).

The IL-12 receptor (IL-12R) is a heterodimeric complex consisting ofIL-12Rβ1 and IL-12Rβ2 chains expressed on the surface of activatedT-cells and natural killer cells (Trinchieri et al.,2003). The IL-12Rβ1chain binds to the IL-12p40 subunit, whereas IL-12p35 in associationwith IL-12Rβ2 confers an intracellular signaling ability (Benson et al.,2011). Signal transduction through IL-12R induces phosphorylation ofJanus kinase (Jak2) and tyrosine kinase (Tyk2), that phosphorylate andactivate signal transducer and activator of transcription (STAT)1,STAT3, STAT4, and STATS. The specific cellular effects of IL-12 are duemainly to activation of STAT4. IL-12 induces natural killer and T-cellsto produce cytokines, in particular interferon (IFN)γ, that mediate manyof the proinflammatory activities of IL-12, including CD4+ T-celldifferentiation toward the Th1 phenotype (Montepaone et al., 2014).

Regulatory T cells actively suppress activation of the immune system andprevent pathological self-reactivity and consequent autoimmune disease.Developing drugs and methods to selectively activate regulatory T cellsfor the treatment of autoimmune disease is the subject of intenseresearch and, until the development of the present invention, which canselectively deliver active interleukins at the site of inflammation, hasbeen largely unsuccessful. Regulatory T cells (Treg) are a class ofCD4+CD25+ T cells that suppress the activity of other immune cells. Tregare central to immune system homeostasis, and play a major role inmaintaining tolerance to self-antigens and in modulating the immuneresponse to foreign antigens. Multiple autoimmune and inflammatorydiseases, including Type 1 Diabetes (T1D), Systemic Lupus Erythematosus(SLE), and Graft-versus-Host Disease (GVHD) have been shown to have adeficiency of Treg cell numbers or Treg function.

Consequently, there is great interest in the development of therapiesthat boost the numbers and/or function of Treg cells. One treatmentapproach for autoimmune diseases being investigated is thetransplantation of autologous, ex vivo-expanded Treg cells (Tang, Q., etal, 2013, Cold Spring Harb. Perspect. Med., 3:1-15). While this approachhas shown promise in treating animal models of disease and in severalearly stage human clinical trials, it requires personalized treatmentwith the patient's own T cells, is invasive, and is technically complex.Another approach is treatment with low dose Interleukin-2 (IL-2). Tregcells characteristically express high constitutive levels of the highaffinity IL-2 receptor, IL2Rαβγ, which is composed of the subunits IL2Rα(CD25), IL2Rβ (CD122), and IL2Rγ (CD132), and Treg cell growth has beenshown to be dependent on IL-2 (Malek, T. R., et al., 2010, Immunity,33:153-65).

Conversely, immune activation has also been achieved using IL-2, andrecombinant IL-2 (Proleukin®) has been approved to treat certaincancers. High-dose IL-2 is used for the treatment of patients withmetastatic melanoma and metastatic renal cell carcinoma with a long-termimpact on overall survival.

Clinical trials of low-dose IL-2 treatment of chronic GVHD (Koreth, J.,et al., 2011, N Engl J Med., 365:2055-66) and HCV-associated autoimmunevasculitis patients (Saadoun, D., et al., 2011, N Engl J Med.,365:2067-77) have demonstrated increased Treg levels and signs ofclinical efficacy. New clinical trials investigating the efficacy ofIL-2 in multiple other autoimmune and inflammatory diseases have beeninitiated. The rationale for using so-called low dose IL-2 was toexploit the high IL-2 affinity of the trimeric IL-2 receptor which isconstitutively expressed on Tregs while leaving other T cells which donot express the high affinity receptor in the inactivated state.Aldesleukin (marketed as Proleukin® by Prometheus Laboratories, SanDiego, Calif.), the recombinant form of IL-2 used in these trials, isassociated with high toxicity. Aldesleukin, at high doses, is approvedfor the treatment of metastatic melanoma and metastatic renal cancer,but its side effects are so severe that its use is only recommended in ahospital setting with access to intensive care (Web address:www.proleukin.com/assets/pdf/proleukin.pdf).

The clinical trials of IL-2 in autoimmune diseases have employed lowerdoses of IL-2 in order to target Treg cells, because Treg cells respondto lower concentrations of IL-2 than many other immune cell types due totheir expression of IL2R alpha (Klatzmann D, 2015 Nat Rev Immunol.15:283-94). However, even these lower doses resulted in safety andtolerability issues, and the treatments used have employed dailysubcutaneous injections, either chronically or in intermittent 5-daytreatment courses. Therefore, there is a need for an autoimmune diseasetherapy that potentiates Treg cell numbers and function, that targetsTreg cells more specifically than IL-2, that is safer and moretolerable, and that is administered less frequently.

One approach that has been suggested for improving the therapeutic indexof IL-2-based therapy for autoimmune diseases is to use variants of IL-2that are selective for Treg cells relative to other immune cells. IL-2receptors are expressed on a variety of different immune cell types,including T cells, NK cells, eosinophils, and monocytes, and this broadexpression pattern likely contributes to its pleiotropic effect on theimmune system and high systemic toxicity. In particular, activated Teffector cells express IL2Rαβγ, as do pulmonary epithelial cells. But,activating T effector cells runs directly counter to the goal ofdown-modulating and controlling an immune response, and activatingpulmonary epithelial cells leads to known dose-limiting side effects ofIL-2 including pulmonary edema. In fact, the major side effect ofhigh-dose IL-2 immunotherapy is vascular leak syndrome (VLS), whichleads to accumulation of intravascular fluid in organs such as lungs andliver with subsequent pulmonary edema and liver cell damage. There is notreatment of VLS other than withdrawal of IL-2. Low-dose IL-2 regimenshave been tested in patients to avoid VLS, however, at the expense ofsuboptimal therapeutic results.

According to the literature, VLS is believed to be caused by the releaseof proinflammatory cytokines from IL-2-activated NK cells. However,there is some evidence that pulmonary edema results from direct bindingof IL-2 to lung endothelial cells, which expressed low to intermediatelevels of functional αβγ IL-2Rs. And, the pulmonary edema associatedwith interaction of IL-2 with lung endothelial cells was abrogated byblocking binding to CD25 with an anti-CD25 monoclonal antibody (mAb), inCD25-deficient host mice, or by the use of CD122-specific IL-2/anti-IL-2mAb (IL-2/mAb) complexes, thus preventing VLS.

Treatment with interleukin cytokines other than IL-2 has been morelimited. IL-15 displays immune cell stimulatory activity similar to thatof IL-2 but without the same inhibitory effects, thus making it apromising immunotherapeutic candidate. Clinical trials of recombinanthuman IL-15 for the treatment of metastatic malignant melanoma or renalcell cancer demonstrated appreciable changes in immune celldistribution, proliferation, and activation and suggested potentialantitumor activity (Conlon et. al., 2014). IL-15 is currently inclinical trials to treat various forms of cancer. However, IL-15 therapyis known to be associated with undesired and toxic effects, such asexacerbating certain leukemias, graft-versus-host disease, hypotension,thrombocytopenia, and liver injury. (Mishra A., et al., Cance Cell,2012, 22(5):645-55; Alpdogan O. et al., Blood, 2005, 105(2):866-73;Conlon KC et al., J Clin Oncol, 2015, 33(1):74-82.)

IL-7 promotes lymphocyte development in the thymus and maintainssurvival of naive and memory T cell homeostasis in the periphery.Moreover, it is important for the organogenesis of lymph nodes (LN) andfor the maintenance of activated T cells recruited into the secondarylymphoid organs (SLOs) (Gao et. al., 2015). In clinical trials of IL-7,patients receiving IL-7 showed increases in both CD4+ and CD8+ T cells,with no significant increase in regulatory T cell numbers as monitoredby FoxP3 expression (Sportes et al., 2008). In clinical trials reportedin 2006, 2008 and 2010, patients with different kinds of cancers such asmetastatic melanoma or sarcoma were injected subcutaneously withdifferent doses of IL-7. Little toxicity was seen except for transientfevers and mild erythema. Circulating levels of both CD4+ and CD8+ Tcells increased significantly and the number of Treg reduced. TCRrepertoire diversity increased after IL-7 therapy. However, theanti-tumor activity of IL-7 was not well evaluated (Gao et. al., 2015).Results suggest that IL-7 therapy could enhance and broaden immuneresponses.

IL-12 is a pleiotropic cytokine, the actions of which create aninterconnection between the innate and adaptive immunity. IL-12 wasfirst described as a factor secreted from PMA-induced EBV-transformedB-cell lines. Based on its actions, IL-12 has been designated ascytotoxic lymphocyte maturation factor and natural killer cellstimulatory factor. Due to bridging the innate and adaptive immunity andpotently stimulating the production of IFNγ, a cytokine coordinatingnatural mechanisms of anticancer defense, IL-12 seemed ideal candidatefor tumor immunotherapy in humans. However, severe side effectsassociated with systemic administration of IL-12 in clinicalinvestigations and the very narrow therapeutic index of this cytokinemarkedly tempered enthusiasm for the use of this cytokine in cancerpatients (Lasek et. al., 2014). Approaches to IL-12 therapy in whichdelivery of the cytokine is tumor-targeted, which may diminish some ofthe previous issues with IL-12 therapy, are currently in clinical trialsfor cancers.

The direct use of IL-2 as an agonist to bind the IL-2R and modulateimmune responses therapeutically has been problematic due itswell-documented therapeutic risks, e.g., its short serum half-life andhigh toxicity. These risks have also limited the therapeutic developmentand use of other cytokines. New forms of cytokines that reduce theserisks are needed. Disclosed herein are compositions and methodscomprising IL-2 and IL-15 and other cytokines, functional fragments andmuteins of cytokines as well as conditionally active cytokines designedto address these risks and provide needed immunomodulatory therapeutics.

The present invention is designed to address the shortcomings of directIL-2 therapy and therapy using other cytokines, for example usingcytokine blocking moieties, e.g. steric blocking polypeptides, serumhalf-life extending polypeptides, targeting polypeptides, linkingpolypeptides, including protease cleavable linkers, and combinationsthereof. Cytokines, including interleukins (e.g., IL-2, IL-7, IL-12,IL-15, IL-18, IL-21 IL-23), interferons (IFNs, including IFNalpha,IFNbeta and IFNgamma), tumor necrosis factors (e.g., TNFalpha,lymphotoxin), transforming growth factors (e.g., TGFbeta1l, TGFbeta2,TGFbeta3), chemokines (C-X-C motif chemokine 10 (CXCL10), CCL19, CCL20,CCL21), and granulocyte macrophage-colony stimulating factor (GM-CS) arehighly potent when administered to patients. As used herein, “chemokine”means a family of small cytokines with the ability to induce directedchemotaxis in nearby responsive cells Cytokines can provide powerfultherapy, but are accompanied by undesired effects that are difficult tocontrol clinically and which have limited the clinical use of cytokines.This disclosure relates to new forms of cytokines that can be used inpatients with reduced or eliminated undesired effects. In particular,this disclosure relates to pharmaceutical compositions includingchimeric polypeptides (fusion proteins), nucleic acids encoding fusionproteins and pharmaceutical formulations of the foregoing that containcytokines or active fragments or muteins of cytokines that havedecreased cytokine receptor activating activity in comparison to thecorresponding cytokine. However, under selected conditions or in aselected biological environment the chimeric polypeptides activate theircognate receptors, often with the same or higher potency as thecorresponding naturally occurring cytokine. As described herein, this istypically achieved using a cytokine blocking moiety that blocks orinhibits the receptor activating function of the cytokine, activefragment or mutein thereof under general conditions but not underselected conditions, such as those present at the desired site ofcytokine activity (e.g., an inflammatory site ora tumor).

The chimeric polypeptides and nucleic acids encoding the chimericpolypeptides can be made using any suitable method. For example, nucleicacids encoding a chimeric polypeptide can be made using recombinant DNAtechniques, synthetic chemistry or combinations of these techniques, andexpressed in a suitable expression system, such as in CHO cells.Chimeric polypeptides can similarly be made, for example by expressionof a suitable nucleic acid, using synthetic or semi-synthetic chemicaltechniques, and the like. In some embodiments, the blocking moiety canbe attached to the cytokine polypeptide via sortase-mediatedconjugation. “Sortases” are transpeptidases that modify proteins byrecognizing and cleaving a carboxyl-terminal sorting signal embedded inor terminally attached to a target protein or peptide. Sortase Acatalyzes the cleavage of the LPXTG motif (SEQ ID No.: 442) (where X isany standard amino acid) between the Thr and Gly residue on the targetprotein, with transient attachment of the Thr residue to the active siteCys residue on the enzyme, forming an enzyme-thioacyl intermediate. Tocomplete transpeptidation and create the peptide-monomer conjugate, abiomolecule with an N-terminal nucleophilic group, typically anoligoglycine motif, attacks the intermediate, displacing Sortase A andjoining the two molecules.

To form the cytokine-blocking moiety fusion protein, the cytokinepolypeptide is first tagged at the N-terminus with a polyglycinesequence, or alternatively, with at the C-terminus with a LPXTG motif(SEQ ID NO.: 442). The blocking moiety or other element has respectivepeptides attached that serve as acceptor sites for the taggedpolypeptides. For conjugation to domains carrying a LPXTG (SEQ ID NO.:442) acceptor peptide attached via its N-terminus, the polypeptide willbe tagged with an N-terminal poly-glycine stretch. For conjugation todomain carrying a poly-glycine peptide attached via its C-terminus, thepolypeptide will be tagged at its C-terminus with a LPXTG (SEQ ID NO.:442) sortase recognition sequence. Recognizing poly-glycine and LPXTG(SEQ ID NO.: 442) sequences, sortase will form a peptide bond betweenpolymer-peptide and tagged polypeptides. The sortase reaction cleavesoff glycine residues as intermediates and occurs at room temperature.

A variety of mechanisms can be exploited to remove or reduce theinhibition caused by the blocking moiety. For example, thepharmaceutical compositions can include a cytokine moiety and a blockingmoiety, e.g. a steric blocking moiety, with a protease cleavable linkercomprising a protease cleavage site located between the cytokine andcytokine blocking moiety or within the cytokine blocking moiety. Whenthe protease cleavage site is cleaved, the blocking moiety candissociate from cytokine, and the cytokine can then activate cytokinereceptor. A cytokine moiety can also be blocked by a specific blockingmoiety, such as an antibody, which binds an epitope found on therelevant cytokine.

Any suitable linker can be used. For example, the linker can compriseglycine-glycine, a sortase-recognition motif, or a sortase-recognitionmotif and a peptide sequence (Gly₄Ser)_(n). (SEQ ID NO.: 443) or(Gly₃Ser)_(n), (SEQ ID NO.: 444) wherein n is 1, 2, 3, 4 or 5.Typically, the sortase-recognition motif comprises a peptide sequenceLPXTG (SEQ ID NO.: 442), where X is any amino acid. In some embodiments,the covalent linkage is between a reactive lysine residue attached tothe C-terminal of the cytokine polypeptide and a reactive aspartic acidattached to the N-terminal of the blocker or other domain. In otherembodiments, the covalent linkage is between a reactive aspartic acidresidue attached to the N-terminal of the cytokine polypeptide and areactive lysine residue attached to the C-terminal of said blocker orother domain.

Accordingly, as described in detail herein, the cytokine blockingmoieties used can be steric blockers. As used herein, a “steric blocker”refers to a polypeptide or polypeptide moiety that can be covalentlybonded to a cytokine polypeptide directly or indirectly through othermoieties such as linkers, for example in the form of a chimericpolypeptide (fusion protein), but otherwise does not covalently bond tothe cytokine polypeptide. A steric blocker can non-covalently bond tothe cytokine polypeptide, for example though electrostatic, hydrophobic,ionic or hydrogen bonding. A steric blocker typically inhibits or blocksthe activity of the cytokine moiety due to its proximity to the cytokinemoiety and comparative size. The steric inhibition of the cytokinemoiety can be removed by spatially separating the cytokine moiety fromthe steric blocker, such as by enzymatically cleaving a fusion proteinthat contains a steric blocker and a cytokine polypeptide at a sitebetween the steric blocker and the cytokine polypeptide.

As described in greater detail herein, the blocking function can becombined with or due to the presence of additional functional componentsin the pharmaceutical composition, such as a targeting domain, a serumhalf-life extension element, and protease-cleavable linkingpolypeptides. For example, a serum half-life extending polypeptide canalso be a steric blocker.

In the interest of presenting a concise disclosure of the full scope ofthe invention, aspects of the invention are described in detail usingthe cytokine IL-2 as an exemplary cytokine. However, the invention andthis disclosure are not limited to IL-2. It will be clear to a person ofskill in the art that this disclosure, including the disclosed methods,polypeptides and nucleic acids, adequately describes and enables the useof other cytokines, fragments and muteins, such as IL-2, IL-7, IL-12,IL-15, IL-18, IL-21 IL-23, IFNalpha, IFNbeta, IFNgamma, TNFalpha,lymphotoxin, TGF-beta1, TGFbeta2, TGFbeta3, GM-CSF, CXCL10, CCL19,CCL20, CCL21 and functional fragments or muteins of any of theforegoing.

Various elements ensure the delivery and activity of IL-2 preferentiallyat the site of desired IL-2 activity and to severely limit systemicexposure to the interleukin via a blocking and/or a targeting strategypreferentially linked to a serum half-life extension strategy. In thisserum half-life extension strategy, the blocked version of interleukincirculates for extended times (preferentially 1-2 or more weeks) but theactivated version has the typical serum half-life of the interleukin.

By comparison to a serum half-life extended version, the serum half-lifeof IL-2 administered intravenously is only ˜10 minutes due todistribution into the total body extracellular space, which is large,˜15 L in an average sized adult. Subsequently, IL-2 is metabolized bythe kidneys with a half-life of ∧2.5 hours. (Smith, K. “Interleukin 2immunotherapy.” Therapeutic Immunology 240 (2001)). By othermeasurements, IL-2 has a very short plasma half-life of 85 minutes forintravenous administration and 3.3 hours subcutaneous administration(Kirchner, G. I., et al., 1998, Br J Clin Pharmacol. 46:5-10). In someembodiments of this invention, the half-life extension element is linkedto the interleukin via a linker which is cleaved at the site of action(e.g. by inflammation-specific or tumor-specific proteases) releasingthe interleukin's full activity at the desired site and also separatingit from the half-life extension of the uncleaved version. In suchembodiments, the fully active and free interleukin would have verydifferent pharmacokinetic (pK) properties—a half-life of hours insteadof weeks. In addition, exposure to active cytokine is limited to thesite of desired cytokine activity (e.g., an inflammatory site or tumor)and systemic exposure to active cytokine, and associated toxicity andside effects, are reduced.

Other cytokines envisioned in this invention have similar pharmacology(e.g. IL-15 as reported by Blood 2011 117:4787-4795; doi:doi.org/10.1182/blood-2010-10-311456) as IL-2 and accordingly, thedesigns of this invention address the shortcomings of using these agentsdirectly, and provide chimeric polypeptides that can have extendedhalf-life and/or be targeted to a site of desired activity (e.g., a siteof inflammation or a tumor).

If desired, IL-2 can be engineered to bind the IL-2R complex generallyor one of the three IL-2R subunits specifically with an affinity thatdiffers from that of the corresponding wild-type IL-2, for example toselectively activate Tregs or Teff. For example, IL-2 polypeptides thatare said to have higher affinity for the trimeric form of the IL-2receptor relative to the dimeric beta/gamma form of the 11-2 receptor incomparison to wild type IL-2 can have an amino acid sequence thatincludes one of the following sets of mutations with respect to SEQ IDNO:1 (a mature IL-2 protein comprising amino acids 21-153 of human IL-2having the Uniprot Accession No. P60568-1): (a) K64R, V69A, and Q74P;(b) V69A, Q74P, and T101A; (c) V69A, Q74P, and I128T; (d) N30D, V69A,Q74P, and F103; (e) K49E, V69A, A73V, and K76E; (f) V69A, Q74P, T101A,and T133N; (g) N305, V69A, Q74P, and I128A; (h) V69A, Q74P, N88D, andS99P; (i) N30S, V69A, Q74P, and I128T; (j) K9T, Q11R, K35R, V69A, andQ74P; (k) A1T, M46L, K49R, E61D, V69A, and H79R; (1) K48E, E68D, N71T,N90H, F103S, and I114V; (m) S4P, T10A, Q11R, V69A, Q74P, N88D, andT133A; (n) E15K, N30S Y31H, K35R, K48E, V69A, Q74P, and I92T; (o) N30S,E68D, V69A, N71A, Q74P, S75P, K76R, and N90H; (p) N30S, Y31C, T37A,V69A, A73V, Q74P, H79R, and I128T; (q) N26D, N29S, N30S, K54R, E67G,V69A, Q74P, and I92T; (r) K8R, Q13R, N26D, N30T, K35R, T37R, V69A, Q74P,and I92T; and (s) N29S, Y31H, K35R, T37A, K48E, V69A, N71R, Q74P, N88D,and I89V. This approach can also be applied to prepare muteins of othercytokines including interleukins (e.g., IL-2, IL-7, IL-12, IL-15, IL-18,IL-23), interferons (IFNs, including IFNalpha, IFNbeta and IFNgamma),tumor necrosis factors (e.g., TNFalpha, lymphotoxin), transforminggrowth factors (e.g., TGFbeta1, TGFbeta2, TGFbeta3) and granulocytemacrophage-colony stimulating factor (GM-CS). For example, muteins canbe prepared that have desired binding affinity for a cognate receptor.

As noted above, any of the mutant IL-2 polypeptides disclosed herein caninclude the sequences described; they can also be limited to thesequences described and otherwise identical to SEQ ID NO:1. Moreover,any of the mutant IL-2 polypeptides disclosed herein can optionallyinclude a substitution of the cysteine residue at position 125 withanother residue (e.g., serine) and/or can optionally include a deletionof the alanine residue at position 1 of SEQ ID NO:1.

Another approach to improving the therapeutic index of an IL-2 basedtherapy is to optimize the pharmacokinetics of the molecule to maximallyactivate Treg cells. Early studies of IL-2 action demonstrated that IL-2stimulation of human T cell proliferation in vitro required a minimum of5-6 hours exposure to effective concentrations of IL-2 (Cantrell, D. A.,et. al., 1984, Science, 224: 1312-1316). When administered to humanpatients, IL-2 has a very short plasma half-life of 85 minutes forintravenous administration and 3.3 hours subcutaneous administration(Kirchner, G. I., et al., 1998, Br J Clin Pharmacol. 46:5-10). Becauseof its short half-life, maintaining circulating IL-2 at or above thelevel necessary to stimulate T cell proliferation for the necessaryduration necessitates high doses that result in peak IL-2 levelssignificantly above the EC50 for Treg cells or will require frequentadministration. These high IL-2 peak levels can activate IL2Rβγreceptors and have other unintended or adverse effects, for example VLSas noted above. An IL-2 analog, or a multifunctional protein with IL-2attached to a domain that enables binding to the FcRn receptor, with alonger circulating half-life than IL-2 can achieve a target drugconcentration for a specified period of time at a lower dose than IL-2,and with lower peak levels. Such an IL-2 analog will therefore requireeither lower doses or less frequent administration than IL-2 toeffectively stimulate Treg cells. Less frequent subcutaneousadministration of an IL-2 drug will also be more tolerable for patients.A therapeutic with these characteristics will translate clinically intoimproved pharmacological efficacy, reduced toxicity, and improvedpatient compliance with therapy. Alternatively, IL-2 or muteins of IL-2(herein, “IL-2*”) can be selectively targeted to the intended site ofaction (e.g. sites of inflammation or a tumor). This targeting can beachieved by one of several strategies, including the addition of domainsto the administered agent that comprise blockers of the IL-2 (ormuteins) that are cleaved away or by targeting domains or a combinationof the two.

In some embodiments, IL-2* partial agonists can be tailored to bind withhigher or lower affinity depending on the desired target; for example,an IL-2* can be engineered to bind with enhanced affinity to one of thereceptor subunits and not the others. These types of partial agonists,unlike full agonists or complete antagonists, offer the ability to tunethe signaling properties to an amplitude that elicits desired functionalproperties while not meeting thresholds for undesired properties. Giventhe differential activities of the partial agonists, a repertoire ofIL-2 variants could be engineered to exhibit an even finer degree ofdistinctive signaling activities, ranging from almost full to partialagonism to complete antagonism.

In some embodiments, the IL-2* has altered affinity for IL-2Rα. In someembodiments, the IL-2* has a higher affinity for IL-2Rα than wild-typeIL-2. In other embodiments, the IL-2* has altered affinity for IL-2Rβ.In one embodiment, IL-2* has enhanced binding affinity for IL-2Rβ, e.g.,the N-terminus of IL-2Rβ, that eliminates the functional requirement forIL-2Rα. In another embodiment, an IL-2* is generated that has increasedbinding affinity for IL-2Rβ but that exhibited decreased binding toIL-2Rγ, and thereby is defective IL-2Rβ heterodimerization andsignaling.

Blocking moieties, described in further detail below, can also be usedto favor binding to or activation of one or more receptors. In oneembodiment, blocking moieties are added such that IL-2Rβγ binding oractivation is blocked but IL-2Rα binding or activation is not changed.In another embodiment, blocking moieties are added such that IL-2Rαbinding or activation is diminished. In another embodiment, blockingmoieties are added such that binding to and or activation of all threereceptors is inhibited. This blocking may be relievable by removal ofthe blocking moieties in a particular environment, for example byproteolytic cleavage of a linker linking one or more blocking moietiesto the cytokine.

A similar approach can be applied to improve other cytokines,particularly for use as immunostimulatory agents, for example fortreating cancer. For example, in this aspect, the pharmacokineticsand/or pharmacodynamics of the cytokine (e.g., IL-2, IL-7, IL-12, IL-15,IL-18, IL-21 IL-23, IFNalpha, IFNbeta and IFNgamma, TNFalpha,lymphotoxin, TGFbeta1, TGFbeta2, TGFbeta3 GM-CSF, CXCL10, CCL19, CCL20,and CCL21 can be tailored to maximally activate effector cells (e.g.,effect T cells, NK cells) and/or cytotoxic immune response promotingcells (e.g., induce dendritic cell maturation) at a site of desiredactivity, such as in a tumor, but preferably not systemically.

Thus, provided herein are pharmaceutical compositions comprising atleast one cytokine polypeptide, such as interleukins (e.g., IL-2, IL-7,IL-12, IL-15, IL-18, IL-21, IL-23), interferons (IFNs, includingIFNalpha, IFNbeta and IFNgamma), tumor necrosis factors (e.g., TNFalpha,lymphotoxin), transforming growth factors (e.g., TGFbeta1, TGFbeta2,TGFbeta3), chemokines (e.g. CXCL10, CCL19, CCL20, CCL21) and granulocytemacrophage-colony stimulating factor (GM-CS) or a functional fragment ormutein of any of the foregoing. The polypeptide typically also includesat least one linker amino acid sequence, wherein the amino acid sequenceis in certain embodiments capable of being cleaved by an endogenousprotease. In one embodiment, the linker comprises an amino acid sequencecomprising HSSKLQ (SEQ ID NO.: 25), GPLGVRG (SEQ ID NO.: 445), IPVSLRSG(SEQ ID NO.: 446), VPLSLYSG (SEQ ID NO. 447), or SGESPAYYTA (SEQ ID NO.448). In other embodiments, the chimeric polypeptide further contains ablocking moiety, e.g. a steric blocking polypeptide moiety, capable ofblocking the activity of the interleukin polypeptide. The blockingmoiety, for example, can comprise a human serum albumin (HSA) bindingdomain or an optionally branched or multi-armed polyethylene glycol(PEG). Alternatively, the pharmaceutical composition comprises a firstcytokine polypeptide or a fragment thereof, and blocking moiety, e.g. asteric blocking polypeptide moiety, wherein the blocking moiety blocksthe activity of the cytokine polypeptide on the cytokine receptor, andwherein the blocking moiety in certain embodiments comprises a proteasecleavable domain. In some embodiments, blockade and reduction ofcytokine activity is achieved simply by attaching additional domainswith very short linkers to the N or C terminus of the interleukindomain. In such embodiments, it is anticipated the blockade is relievedby protease digestion of the blocking moiety or of the short linker thattethers the blocker to the interleukin. Once the domain is clipped or isreleased, it will no longer be able to achieve blockade of cytokineactivity.

The pharmaceutical composition e.g., chimeric polypeptide can comprisetwo or more cytokines, which can be the same cytokine polypeptide ordifferent cytokine polypeptides. For example, the two or more differenttypes of cytokines have complementary functions. In some examples, afirst cytokine is IL-2 and a second cytokine is IL-12. In someembodiments, each of the two or more different types of cytokinepolypeptides have activities that modulate the activity of the othercytokine polypeptides. In some examples of chimeric polypeptides thatcontain two cytokine polypeptides, a first cytokine polypeptide isT-cell activating, and a second cytokine polypeptide isnon-T-cell-activating. In some examples of chimeric polypeptides thatcontain two cytokine polypeptides, a first cytokine is achemoattractant, e.g. CXCL10, and a second cytokine is an immune cellactivator.

Preferably, the cytokine polypetides (including functional fragments)that are included in the fusion proteins disclosed herein are notmutated or engineered to alter the properties of the naturally occurringcytokine, including receptor binding affinity and specificity or serumhalf-life. However, changes in amino acid sequence from naturallyoccurring (including wild type) cytokine are acceptable to facilitatecloning and to achieve desired expression levels, for example.

Blocking Moiety

The blocking moiety can be any moiety that inhibits the ability of thecytokine to bind and/or activate its receptor. The blocking moiety caninhibit the ability of the cytokine to bind and/or activate its receptorsterically blocking and/or by noncovalently binding to the cytokine.Examples of suitable blocking moieties include the full length or acytokine-binding fragment or mutein of the cognate receptor of thecytokine. Antibodies and fragments thereof including, a polyclonalantibody, a recombinant antibody, a human antibody, a humanized antibodya single chain variable fragment (scFv), single-domain antibody such asa heavγ chain variable domain (VH), a light chain variable domain (VL)and a variable domain of camelid-type nanobody (VHH), a dAb and the likethat bind the cytokine can also be used. Other suitable antigen-bindingdomain that bind the cytokine can also be used, includenon-immunoglobulin proteins that mimic antibody binding and/or structuresuch as, anticalins, affilins, affibody molecules, affimers, affitins,alphabodies, avimers, DARPins, fynomers, kunitz domain peptides,monobodies, and binding domains based on other engineered scaffolds suchas SpA, GroEL, fibronectin, lipocallin and CTLA4 scaffolds. Furtherexamples of suitable blocking polypeptides include polypeptides thatsterically inhibit or block binding of the cytokine to its cognatereceptor. Advantageously, such moieties can also function as half-lifeextending elements. For example, a peptide that is modified byconjugation to a water-soluble polymer, such as PEG, can stericallyinhibit or prevent binding of the cytokine to its receptor.Polypeptides, or fragments thereof, that have long serum half-lives canalso be used, such as serum albumin (human serum albumin),immunoglobulin Fc, transferrin and the like, as well as fragments andmuteins of such polypeptides. Antibodies and antigen-binding domainsthat bind to, for example, a protein with a long serum half-life such asHSA, immunoglobulin or transferrin, or to a receptor that is recycled tothe plasma membrane, such as FcRn or transferrin receptor, can alsoinhibit the cytokine, particularly when bound to their antigen. Examplesof such antigen-binding polypeptides include a single chain variablefragment (scFv), single-domain antibody such as a heavγ chain variabledomain (VH), a light chain variable domain (VL) and a variable domain ofcamelid-type nanobody (VHH), a dAb and the like. Other suitableantigen-binding domain that bind the cytokine can also be used, includenon-immunoglobulin proteins that mimic antibody binding and/or structuresuch as, anticalins, affilins, affibody molecules, affimers, affitins,alphabodies, avimers, DARPins, fynomers, kunitz domain peptides,monobodies, and binding domains based on other engineered scaffolds suchas SpA, GroEL, fibronectin, lipocallin and CTLA4 scaffolds.

In illustrative examples, when IL-2 is the cytokine in the chimericpolypeptide, the blocking moiety can be the full length or fragment ormutein of the alpha chain of IL-2 receptor (IL-2Rα) or beta (IL-2Rβ) orgamma chain of IL-2 receptor (IL-2Rγ), an anti-IL-2 single-domainantibody (dAb) or scFv, a Fab, an anti-CD25 antibody or fragmentthereof, and anti-HAS dAb or scFv, and the like.

In Vivo Half-life Extension Elements

Preferably, the chimeric polypeptides comprise an in vivo half-lifeextension element. Increasing the in vivo half-life of therapeuticmolecules with naturally short half-lives allows for a more acceptableand manageable dosing regimen without sacrificing effectiveness. As usedherein, a “half-life extension element” is a part of the chimericpolypeptide that increases the in vivo half-life and improve pK, forexample, by altering its size (e.g., to be above the kidney filtrationcutoff), shape, hydrodynamic radius, charge, or parameters ofabsorption, biodistribution, metabolism, and elimination. An exemplaryway to improve the pK of a polypeptide is by expression of an element inthe polypeptide chain that binds to receptors that are recycled to theplasma membrane of cells rather than degraded in the lysosomes, such asthe FcRn receptor on endothelial cells and transferrin receptor. Threetypes of proteins, e.g., human IgGs, HSA (or fragments), andtransferrin, persist for much longer in human serum than would bepredicted just by their size, which is a function of their ability tobind to receptors that are recycled rather than degraded in thelysosome. These proteins, or fragments of them that retain the FcRnbinding are routinely linked to other polypeptides to extend their serumhalf-life. In one embodiment, the half-life extension element is a humanserum albumin (HSA) binding domain. HSA (SEQ ID NO: 2) may also bedirectly bound to the pharmaceutical compositions or bound via a shortlinker. Fragments of HSA may also be used. HSA and fragments thereof canfunction as both a blocking moiety and a half-life extension element.Human IgGs and Fc fragments can also carry out a similar function.

The serum half-life extension element can also be antigen-bindingpolypeptide that binds to a protein with a long serum half-life such asserum albumin, transferrin and the like. Examples of such polypeptidesinclude antibodies and fragments thereof including, a polyclonalantibody, a recombinant antibody, a human antibody, a humanized antibodya single chain variable fragment (scFv), single-domain antibody such asa heavγ chain variable domain (VH), a light chain variable domain (VL)and a variable domain of camelid-type nanobody (VHH), a dAb and thelike. Other suitable antigen-binding domain include non-immunoglobulinproteins that mimic antibody binding and/or structure such as,anticalins, affilins, affibody molecules, affimers, affitins,alphabodies, avimers, DARPins, fynomers, kunitz domain peptides,monobodies, and binding domains based on other engineered scaffolds suchas SpA, GroEL, fibronectin, lipocallin and CTLA4 scaffolds. Furtherexamples of antigen-binding polypeptides include a ligand for a desiredreceptor, a ligand-binding portion of a receptor, a lectin, and peptidesthat binds to or associates with one or more target antigens.

Some preferred serum half-life extension elements are polypeptides thatcomprise complementarity determining regions (CDRs), and optionallynon-CDR loops. Advantageously, such serum half-life extension elementscan extend the serum half-life of the cytokine, and also function asinhibitors of the cytokine (e.g., via steric blocking, non-covalentinteraction or combination thereof) and/or as targeting domains. In someinstances, the serum half-life extension elements are domains derivedfrom an immunoglobulin molecule (Ig molecule) or engineered proteinscaffolds that mimic antibody structure and/or binding activity. The Igmay be of any class or subclass (IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgMetc). A polypeptide chain of an Ig molecule folds into a series ofparallel beta strands linked by loops. In the variable region, three ofthe loops constitute the “complementarity determining regions” (CDRs)which determine the antigen binding specificity of the molecule. An IgGmolecule comprises at least two heavy (H) chains and two light (L)chains inter-connected by disulfide bonds, or an antigen bindingfragment thereof. Each heavy chain is comprised of a heavγ chainvariable region (abbreviated herein as VH) and a heavγ chain constantregion. The heavγ chain constant region is comprised of three domains,CH1, CH2 and CH3. Each light chain is comprised of a light chainvariable region (abbreviated herein as VL) and a light chain constantregion. The light chain constant region is comprised of one domain, CL.The VH and VL regions can be further subdivided into regions ofhypervariability, termed complementarity determining regions (CDRs) withare hypervariable in sequence and/or involved in antigen recognitionand/or usually form structurally defined loops, interspersed withregions that are more conserved, termed framework regions (FR). Each VHand VL is composed of three CDRs and four FRs, arranged fromamino-terminus to carboxy-terminus in the following order: FR1, CDR1,FR2, CDR2, FR3, CDR3, FR4. In some embodiments of this disclosure, atleast some or all of the amino acid sequences of FR1, FR2, FR3, and FR4are part of the “non-CDR loop” of the binding moieties described herein.As shown in FIG. 5, a variable domain of an immunoglobulin molecule hasseveral beta strands that are arranged in two sheets. The variabledomains of both light and heavy immunoglobulin chains contain threehypervariable loops, or complementarity-determining regions (CDRs). Thethree CDRs of a V domain (CDR1, CDR2, CDR3) cluster at one end of thebeta barrel. The CDRs are the loops that connect beta strands B-C,C′-C″, and F-G of the immunoglobulin fold, whereas the bottom loops thatconnect beta strands AB, CC', C″ -D and E-F of the immunoglobulin fold,and the top loop that connects the D-E strands of the immunoglobulinfold are the non-CDR loops. In some embodiments of this disclosure, atleast some amino acid residues of a constant domain, CH1, CH2, or CH3,are part of the “non-CDR loop” of the binding moieties described herein.Non-CDR loops comprise, in some embodiments, one or more of AB, CD, EF,and DE loops of a Cl-set domain of an Ig or an Ig-like molecule; AB,CC', EF, FG, BC, and EC' loops of a C2-set domain of an Ig or an Ig-likemolecule; DE, BD, GF, A(A1A2)B, and EF loops of I(Intermediate)-setdomain of an Ig or Ig-like molecule.

Within the variable domain, the CDRs are believed to be responsible forantigen recognition and binding, while the FR residues are considered ascaffold for the CDRs. However, in certain cases, some of the FRresidues play an important role in antigen recognition and binding.Framework region residues that affect Ag binding are divided into twocategories. The first are FR residues that contact the antigen, thus arepart of the binding-site, and some of these residues are close insequence to the CDRs. Other residues are those that are far from theCDRs in sequence, but are in close proximity to it in the 3-D structureof the molecule, e.g., a loop in heavγ chain.

The binding moieties are any kinds of polypeptides. For example, incertain instances the binding moieties are natural peptides, syntheticpeptides, or fibronectin scaffolds, or engineered bulk serum proteins.The bulk serum protein comprises, for example, albumin, fibrinogen, or aglobulin. In some embodiments, the binding moieties are engineeredscaffolds. Engineered scaffolds comprise, for example, sdAb, a scFv, aFab, a VHH, a fibronectin type III domain, immunoglobulin-like scaffold(as suggested in Halaby et al., 1999. Prot Eng 12(7):563-571), DARPin,cystine knot peptide, lipocalin, three-helix bundle scaffold, proteinG-related albumin-binding module, or a DNA or RNA aptamer scaffold.

In some cases, the serum half-life extending element comprises a bindingsite for a bulk serum protein. In some embodiments, the CDRs provide thebinding site for the bulk serum protein. The bulk serum protein is, insome examples, a globulin, albumin, transferrin, IgG1, IgG2, IgG4, IgG3,IgA monomer, Factor XIII, Fibrinogen, IgE, or pentameric IgM. In someembodiments, the CDR form a binding site for an immunoglobulin lightchain, such as an Igκ free light chain or an Igλ, free light chain.

The serum half-life extension element can be any type of binding domain,including but not limited to, domains from a monoclonal antibody, apolyclonal antibody, a recombinant antibody, a human antibody, ahumanized antibody. In some embodiments, the binding moiety is a singlechain variable fragment (scFv), single-domain antibody such as a heavγchain variable domain (VH), a light chain variable domain (VL) and avariable domain (VHH) of camelid derived nanobody. In other embodiments,the binding moieties are non-Ig binding domains, i.e., antibody mimetic,such as anticalins, affilins, affibody molecules, affimers, affitins,alphabodies, avimers, DARPins, fynomers, kunitz domain peptides, andmonobodies.

In other embodiments, the serum half-life extension element can be awater-soluble polymer or a peptide that is conjugated to a water-solublepolymer, such as PEG. “PEG,” “polyethylene glycol” and “poly(ethyleneglycol)” as used herein, are interchangeable and encompass anynonpeptidic water-soluble poly(ethylene oxide). The term “PEG” alsomeans a polymer that contains a majority, that is to say, greater than50%, of —OCH₂CH₂— repeating subunits. With respect to specific forms,the PEG can take any number of a variety of molecular weights, as wellas structures or geometries such as “branched,” “linear,” “forked,”“multifunctional,” and the like, to be described in greater detailbelow. The PEG is not limited to a particular structure and can belinear (e.g., an end capped, e.g., alkoxy PEG or a bifunctional PEG),branched or multi-armed (e.g., forked PEG or PEG attached to a polyolcore), a dendritic (or star) architecture, each with or without one ormore degradable linkages. Moreover, the internal structure of the PEGcan be organized in any number of different repeat patterns and can beselected from the group consisting of homopolymer, alternatingcopolymer, random copolymer, block copolymer, alternating tripolymer,random tripolymer, and block tripolymer. PEGs can be conjugated topolypeptide and peptides through any suitable method. Typically areactive PEG derivative, such as N-hydroxysuccinamidyl ester PEG, isreacted with a peptide or polypeptide that includes amino acids with aside chain that contains an amine, sulfhydryl, carboxylic acid orhydroxyl functional group, such as cysteine, lysine, asparagine,glutamine, theonine, tyrosine, serine, aspartic acid, and glutamic acid.

Targeting and Retention Domains

For certain applications, it may be desirable to maximize the amount oftime the construct is present in its desired location in the body. Thiscan be achieved by including one further domain in the chimericpolypeptide (fusion protein) to influence its movements within the body.For example, the chimeric nucleic acids can encode a domain that directsthe polypeptide to a location in the body, e.g., tumor cells or a siteof inflammation; this domain is termed a “targeting domain” and/orencode a domain that retains the polypeptide in a location in the body,e.g., tumor cells or a site of inflammation; this domain is termed a“retention domain”. In some embodiments a domain can function as both atargeting and a retention domain. In some embodiments, the targetingdomain and/or retention domain are specific to a protease-richenvironment. In some embodiments, the encoded targeting domain and/orretention domain are specific for regulatory T cells (Tregs), forexample targeting the CCR4 or CD39 receptors. Other suitable targetingand/or retention domains comprise those that have a cognate ligand thatis overexpressed in inflamed tissues, e.g., the IL-1 receptor, or theIL-6 receptor. In other embodiments, the suitable targeting and/orretention domains comprise those who have a cognate ligand that isoverexpressed in tumor tissue, e.g., Epcam, CEA or mesothelin. In someembodiments, the targeting domain is linked to the interleukin via alinker which is cleaved at the site of action (e.g. by inflammation orcancer specific proteases) releasing the interleukin full activity atthe desired site. In some embodiments, the targeting and/or retentiondomain is linked to the interleukin via a linker which is not cleaved atthe site of action (e.g. by inflammation or cancer specific proteases),causing the cytokine to remain at the desired site.

Antigens of choice, in some cases, are expressed on the surface of adiseased cell or tissue, for example a tumor or a cancer cell. Antigensuseful for tumor targeting and retention include but are not limited toEpCAM, EGFR, HER-2, HER-3, c-Met, FOLR1, and CEA. Pharmaceuticalcompositions disclosed herein, also include proteins comprising twotargeting and/or retention domains that bind to two different targetantigens known to be expressed on a diseased cell or tissue. Exemplarypairs of antigen binding domains include but are not limited toEGFR/CEA, EpCAM/CEA, and HER-2/HER-3.

Suitable targeting and/or retention domains include antigen-bindingdomains, such as antibodies and fragments thereof including, apolyclonal antibody, a recombinant antibody, a human antibody, ahumanized antibody a single chain variable fragment (scFv),single-domain antibody such as a heavγ chain variable domain (VH), alight chain variable domain (VL) and a variable domain of camelid-typenanobody (VHH), a dAb and the like. Other suitable antigen-bindingdomain include non-immunoglobulin proteins that mimic antibody bindingand/or structure such as, anticalins, affilins, affibody molecules,affimers, affitins, alphabodies, avimers, DARPins, fynomers, kunitzdomain peptides, monobodies, and binding domains based on otherengineered scaffolds such as SpA, GroEL, fibronectin, lipocallin andCTLA4 scaffolds. Further examples of antigen-binding polypeptidesinclude a ligand for a desired receptor, a ligand-binding portion of areceptor, a lectin, and peptides that binds to or associates with one ormore target antigens.

In some embodiments, the targeting and/or retention domains specificallybind to a cell surface molecule. In some embodiments, the targetingand/or retention domains specifically bind to a tumor antigen. In someembodiments, the targeting polypeptides specifically and independentlybind to a tumor antigen selected from at least one of Fibroblastactivation protein alpha (FAPa), Trophoblast glycoprotein (5T4),Tumor-associated calcium signal transducer 2 (Trop2), Fibronectin EDB(EDB-FN), fibronectin EIIIB domain, CGS-2, EpCAM, EGFR, HER-2, HER-3,cMet, CEA, and FOLR1. In some embodiments, the targeting polypeptidesspecifically and independently bind to two different antigens, whereinat least one of the antigens is a tumor antigen selected from EpCAM,EGFR, HER-2, HER-3, cMet, CEA, and FOLR1.

The targeting and/or retention antigen can be a tumor antigen expressedon a tumor cell. Tumor antigens are well known in the art and include,for example, EpCAM, EGFR, HER-2, HER-3, c-Met, FOLR1, PSMA, CD38, BCMA,and CEA. 5T4, AFP, B7-H3, Cadherin-6, CAIX, CD117, CD123, CD138, CD166,CD19, CD20, CD205, CD22, CD30, CD33, CD352, CD37, CD44, CD52, CD56,CD70, CD71, CD74, CD79b, DLL3, EphA2, FAP, FGFR2, FGFR3, GPC3, gpA33,FLT-3, gpNMB, HPV-16 E6, HPV-16 E7, ITGA2, ITGA3, SLC39A6, MAGE,mesothelin, Mucl, Muc16, NaPi2b, Nectin-4, P-cadherin, NY-ESO-1, PRLR,PSCA, PTK7, ROR1, SLC44A4, SLTRK5, SLTRK6, STEAP1, TIM1, Trop2, WT1.

The targeting and/or retention antigen can be an immune checkpointprotein. Examples of immune checkpoint proteins include but are notlimited to CD27, CD137, 2B4, TIGIT, CD155, ICOS, HVEM, CD40L, LIGHT,TIM-1, OX40, DNAM-1, PD-L1, PD1, PD-L2, CTLA-4, CD8, CD40, CEACAM1,CD48, CD70, A2AR, CD39, CD73, B7-H3, B7-H4, BTLA, IDO1, IDO2, TDO, KIR,LAG-3, TIM-3, or VISTA.

The targeting and/or retention antigen can be a cell surface moleculesuch as a protein, lipid or polysaccharide. In some embodiments, atargeting and/or retention antigen is a on a tumor cell, virallyinfected cell, bacterially infected cell, damaged red blood cell,arterial plaque cell, inflamed or fibrotic tissue cell. The targetingand/or retention antigen can comprise an immune response modulator.Examples of immune response modulator include but are not limited togranulocyte-macrophage colony stimulating factor (GM-CSF), macrophagecolony stimulating factor (M-CSF), granulocyte colony stimulating factor(G-CSF), interleukin 2 (IL-2), interleukin 3 (IL-3), interleukin 12(IL-12), interleukin 15 (IL-15), B7-1 (CD80), B7-2 (CD86), GITRL, CD3,or GITR.

The targeting and/or retention antigen can be a cytokine receptor.Examples, of cytokine receptors include but are not limited to Type Icytokine receptors, such as GM-CSF receptor, G-CSF receptor, Type I ILreceptors, Epo receptor, LIF receptor, CNTF receptor, TPO receptor; TypeII Cytokine receptors, such as IFN-alpha receptor (IFNAR1, IFNAR2),IFB-beta receptor, IFN-gamma receptor (IFNGR1, IFNGR2), Type II ILreceptors; chemokine receptors, such as CC chemokine receptors, CXCchemokine receptors, CX3C chemokine receptors, XC chemokine receptors;tumor necrosis receptor superfamily receptors, such as TNFRSF5/CD40,TNFRSF8/CD30, TNFRSF7/CD27, TNFRSF1A/TNFR1/CD120a,TNFRSF1B/TNFR2/CD120b; TGF-beta receptors, such as TGF-beta receptor 1,TGF-beta receptor 2; Ig super family receptors, such as IL-1 receptors,CSF-1R, PDGFR (PDGFRA, PDGFRB), SCFR.

Linkers

As stated above, the pharmaceutical compositions comprise one or morelinker sequences. A linker sequence serves to provide flexibilitybetween polypeptides, such that, for example, the blocking moiety iscapable of inhibiting the activity of the cytokine polypeptide. Thelinker sequence can be located between any or all of the cytokinepolypeptide, the serum half-life extension element, and/or the blockingmoiety. As described herein at least one of the linkers is proteasecleavable, and contains a (one or more) cleavage site for a (one ormore) desired protease. Preferably, the desired protease is enriched orselectively expressed at the desired site of cytokine activity (e.g.,the tumor microenvironment). Thus, the fusion protein is preferentiallyor selectively cleaved at the site of desired cytokine activity.

Suitable linkers can be of different lengths, such as from 1 amino acid(e.g., Gly) to 20 amino acids, from 2 amino acids to 15 amino acids,from 3 amino acids to 12 amino acids, including 4 amino acids to 10amino acids, amino acids to 9 amino acids, 6 amino acids to 8 aminoacids, or 7 amino acids to 8 amino acids, and may be 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60amino acids.

The orientation of the components of the pharmaceutical composition, arelargely a matter of design choice and it is recognized that multipleorientations are possible and all are intended to be encompassed by thisdisclosure. For example, a blocking moiety can be located C-terminallyor N-terminally to a cytokine polypeptide.

Proteases known to be associated with diseased cells or tissues includebut are not limited to serine proteases, cysteine proteases, aspartateproteases, threonine proteases, glutamic acid proteases,metalloproteases, asparagine peptide lyases, serum proteases,cathepsins, Cathepsin B, Cathepsin C, Cathepsin D, Cathepsin E,Cathepsin K, Cathepsin L, kallikreins, hKl, hK10, hK15, plasmin,collagenase, Type IV collagenase, stromelysin, Factor Xa,chymotrypsin-like protease, trypsin-like protease, elastase-likeprotease, subtilisin-like protease, actinidain, bromelain, calpain,caspases, caspase-3, Mirl-CP, papain, HIV-1 protease, HSV protease, CMVprotease, chymosin, refill, pepsin, matriptase, legumain, plasmepsin,nepenthesin, metalloexopeptidases, metalloendopeptidases, matrixmetalloproteases (MMP), MMP1, MMP2, MMP3, MMP8, MMP9, MMP13, MMP11,MMP14, urokinase plasminogen activator (uPA), enterokinase,prostate-specific antigen (PSA, hK3), interleukin-1β converting enzyme,thrombin, FAP (FAP-a), dipeptidyl peptidase, meprins, granzymes anddipeptidyl peptidase IV (DPPIV/CD26). Proteases capable of cleavingamino acid sequences encoded by the chimeric nucleic acid sequencesprovided herein can, for example, be selected from the group consistingof a prostate specific antigen (PSA), a matrix metalloproteinase (MMP),an A Disintigrin and a Metalloproteinase (ADAM), a plasminogenactivator, a cathepsin, a caspase, a tumor cell surface protease, and anelastase. The MMP can, for example, be matrix metalloproteinase 2 (MMP2)or matrix metalloproteinase 9 (MMP9).

Proteases useful in the methods disclosed herein are presented in Table1, and exemplary proteases and their cleavage site are presented inTable 1a:

TABLE 1 Proteases relevant to inflammation and cancer ProteaseSpecificity Other aspects Secreted by killer T cells: Granzyme B (grB)Cleaves after Asp Type of serine protease; strongly residues (asp-ase)implicated in inducing perforin-dependent target cell apoptosis GranzymeA (grA) trypsin-like, cleaves after Type of serine protease; basicresidues Granzyme H (grH) Unknown substrate Type of serine protease;specificity Other granzymes are also secreted by killer T cells, but notall are present in humans Caspase-8 Cleaves after Asp Type of cysteineprotease; plays essential residues role in TCR-induced cellularexpansion- exact molecular role unclear Mucosa-associated Cleaves afterarginine Type of cysteine protease; likely acts both lymphoid tissueresidues as a scaffold and proteolytically active (MALT1) enzyme in theCBM-dependent signaling pathway Tryptase Targets: angiotensin I, Type ofmast cell-specific serine protease; fibrinogen, prourokinase,trypsin-like; resistant to inhibition by TGFβ; preferentiallymacromolecular protease inhibitors cleaves proteins after expressed inmammals due to their lysine or arginine tetrameric structure, with allsites facing residues narrow central pore; also associated withinflammation Associated with inflammation: Thrombin Targets: FGF-2, Typeof serine protease; modulates HB-EGF, Osteo-pontin, activity of vasculargrowth factors, PDGF, VEGF chemokines and extracellular proteins;strengthens VEGF-induced proliferation; induces cell migration;angiogenic factor; regulates hemostasis Chymase Exhibit chymotrypsin-Type of mast cell-specific serine protease like specificity, cleavingproteins after aromatic amino acid residues Carboxypeptidase A Cleavesamino acid Type of zinc-dependent metalloproteinase (MC-CPA) residuesfrom C-terminal end of peptides and proteins Kallikreins Targets: highmolecular Type of serine protease; modulate weight relaxation response;contribute to kininogen, pro-urokinase inflammatory response; fibrindegradation Elastase Targets: E-cadherin, GM- Type of neutrophil serineprotease; CSF, IL-1, IL-2, IL-6, degrades ECM components; regulates IL8,p38^(MAPK), TNFα, VE- inflammatory response; activates pro- cadherinapoptotic signaling Cathepsin G Targets: EGF, ENA-78, Type of serineprotease; degrades ECM IL-8, MCP-1, MMP-2, components; chemo-attractantof MT1-MMP, leukocytes; regulates inflammatory PAI-1, RANTES, TGFβ,response; promotes apoptosis TNFα PR-3 Targets: ENA-78, IL-8, Type ofserine protease; promotes IL-18, JNK, p38^(MAPK), inflammatory response;activates pro- TNFα apoptotic signaling Granzyme M (grM) Cleaves afterMet and Type of serine protease; only expressed in other long,unbranched NK cells hydrophobic residues Calpains Cleave between Arg andFamily of cysteine proteases; calcium- Gly dependent; activation isinvolved in the process of numerous inflammation- associated diseases

TABLE 1a Exemplary Proteases and Protease Recognition Sequences CleavageSEQ Domain ID Protease Sequence NO: MMP7 KRALGLPG 3 MMP7(DE)₈RPLALWRS(DR)₈ 4 MMP9 PR(S/T)(L/I)(S/T) 5 MMP9 LEATA 6 MMP11GGAANLVRGG 7 MMP14 SGRIGFLRTA 8 MMP PLGLAG 9 MMP PLGLAX 10 MMPPLGC(me)AG 11 MMP ESPAYYTA 12 MMP RLQLKL 13 MMP RLQLKAC 14MMP2, MMP9, MMP14 EP(Cit)G(Hof)YL 15 Urokinase plasminogen SGRSA 16activator (uPA) Urokinase plasminogen DAFK 17 activator (uPA)Urokinase plasminogen GGGRR 18 activator (uPA) Lysosomal Enzyme GFLG 19Lysosomal Enzyme ALAL 20 Lysosomal Enzyme FK 21 Cathepsin B NLL 22Cathepsin D PIC(Et)FF 23 Cathepsin K GGPRGLPG 24Prostate Specific Antigen HSSKLQ 25 Prostate Specific Antigen HSSKLQL 26Prostate Specific Antigen HSSKLQEDA 27 Herpes Simplex Virus LVLASSSFGY28 Protease HIV Protease GVSQNYPIVG 29 CMV Protease GVVQASCRLA 30Thrombin F(Pip)RS 31 Thrombin DPRSFL 32 Thrombin PPRSFL 33 Caspase-3DEVD 34 Caspase-3 DEVDP 35 Caspase-3 KGSGDVEG 36Interleukin 1β converting GWEHDG 37 enzyme Enterokinase EDDDDKA 38 FAPKQEQNPGST 39 Kallikrein 2 GKAFRR 40 Plasmin DAFK 41 Plasmin DVLK 42Plasmin DAFK 43 TOP ALLLALL 44

Provided herein are pharmaceutical compositions comprising polypeptidesequences. As with all peptides, polypeptides, and proteins, includingfragments thereof, it is understood that additional modifications in theamino acid sequence of the chimeric polypeptides (amino acid sequencevariants) can occur that do not alter the nature or function of thepeptides, polypeptides, or proteins. Such modifications includeconservative amino acid substitutions and are discussed in greaterdetail below.

The compositions provided herein have a desired function. Thecompositions are comprised of at least a cytokine polypeptide, such asIL-2, IL-7, IL-12, IL-15, IL-18, IL-21, IFNa, or IFNγ, or a chemokine,such as CXCL10, CCL19, CCL20, CCL21, a blocking moiety, e.g. a stericblocking polypeptide, and an optional serum half-life extension element,and an optional targeting polypeptide, with one or more linkersconnecting each polypeptide in the composition. The first polypeptide,e.g., an IL-2 mutein, is provided to be an active agent. The blockingmoiety is provided to block the activity of the interleukin. The linkerpolypeptide, e.g., a protease cleavable polypeptide, is provided to becleaved by a protease that is specifically expressed at the intendedtarget of the active agent. Optionally, the blocking moiety blocks theactivity of the first polypeptide by binding the interleukinpolypeptide. In some embodiments, the blocking moiety, e.g. a stericblocking peptide, is linked to the interleukin via a protease-cleavablelinker which is cleaved at the site of action (e.g. byinflammation-specific or tumor-specific proteases) releasing thecytokine full activity at the desired site.

The protease cleavage site may be a naturally occurring proteasecleavage site or an artificially engineered protease cleavage site. Theartificially engineered protease cleavage site can be cleaved by morethan one protease specific to the desired environment in which cleavagewill occur, e.g. a tumor. The protease cleavage site may be cleavable byat least one protease, at least two proteases, at least three proteases,or at least four proteases.

In some embodiments, the linker comprises glycine-glycine, asortase-recognition motif, or a sortase-recognition motif and a peptidesequence (Gly₄Ser)_(n) (SEQ ID NO.: 443) or (Gly₃Ser)_(n) (SEQ ID NO.:444), wherein n is 1, 2, 3, 4 or 5. In one embodiment, thesortase-recognition motif comprises a peptide sequence LPXTG (SEQ IDNO.: 442), where X is any amino acid. In one embodiment, the covalentlinkage is between a reactive lysine residue attached to the C-terminalof the cytokine polypeptide and a reactive aspartic acid attached to theN-terminal of the blocking or other moiety. In one embodiment, thecovalent linkage is between a reactive aspartic acid residue attached tothe N-terminal of the cytokine polypeptide and a reactive lysine residueattached to the C-terminal of the blocking or other moiety.

Cleavage and Inducibility

As described herein, the activity of the cytokine polypeptide thecontext of the fusion protein is attenuated, and protease cleavage atthe desired site of activity, such as in a tumor microenvironment,releases a form of the cytokine from the fusion protein that is muchmore active as a cytokine receptor agonist than the fusion protein. Forexample, the cytokine-receptor activating (agonist) activity of thefusion polypeptide can be at least about 10×, at least about 50×, atleast about 100×, at least about 250×, at least about 500×, or at leastabout 1000× less than the cytokine receptor activating activity of thecytokine polypeptide as a separate molecular entity. The cytokinepolypeptide that is part of the fusion protein exists as a separatemolecular entity when it contains an amino acid that is substantiallyidentical to the cytokine polypeptide and does not substantially includeadditional amino acids and is not associated (by covalent ornon-covalent bonds) with other molecules. If necessary, a cytokinepolypeptide as a separate molecular entity may include some additionalamino acid sequences, such as a tag or short sequence to aid inexpression and/or purification.

In other examples, the cytokine-receptor activating (agonist) activityof the fusion polypeptide is at least about 10×, at least about 50×, atleast about 100×, at least about 250×, at least about 500×, or about1000× less than the cytokine receptor activating activity of thepolypeptide that contains the cytokine polypeptide that is produced bycleavage of the protease cleavable linker in the fusion protein. Inother words, the cytokine receptor activating (agonist) activity of thepolypeptide that contains the cytokine polypeptide that is produced bycleavage of the protease cleavable linker in the fusion protein is atleast about 10×, at least about 50×, at least about 100×, at least about250×, at least about 500×, or at least about 1000× greater than thecytokine receptor activating activity of the fusion protein.

Polypeptide Substitutions

The polypeptides described herein can include components (e.g., thecytokine, the blocking moiety) that have the same amino acid sequence ofthe corresponding naturally occurring protein (e.g., IL-2, IL-15, HSA)or can have an amino acid sequence that differs from the naturallyoccurring protein so long as the desired function is maintained. It isunderstood that one way to define any known modifications andderivatives or those that might arise, of the disclosed proteins andnucleic acids that encode them is through defining the sequence variantsin terms of identity to specific known reference sequences. Specificallydisclosed are polypeptides and nucleic acids which have at least, 70,71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 percent identity to thechimeric polypeptides provided herein. For example, provided arepolypeptides or nucleic acids that have at least, 70, 71, 72, 73, 74,75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92,93, 94, 95, 96, 97, 98, 99 percent identity to the sequence of any ofthe nucleic acids or polypeptides described herein. Those of skill inthe art readily understand how to determine the identity of twopolypeptides or two nucleic acids. For example, the identity can becalculated after aligning the two sequences so that the identity is atits highest level.

Another way of calculating identity can be performed by publishedalgorithms. Optimal alignment of sequences for comparison may beconducted by the local identity algorithm of Smith and Waterman Adv.Appl. Math. 2:482 (1981), by the identity alignment algorithm ofNeedleman and Wunsch, J. Mol. Biol. 48:443 (1970), by the search forsimilarity method of Pearson and Lipman, Proc. Natl. Acad. Sci. USA85:2444 (1988), by computerized implementations of these algorithms(GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics SoftwarePackage, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or byinspection.

The same types of identity can be obtained for nucleic acids by, forexample, the algorithms disclosed in Zuker, Science 244:48-52 (1989);Jaeger et al., Proc. Natl. Acad. Sci. USA 86:7706-7710 (1989); Jaeger etal., Methods Enzymol. 183:281-306 (1989), which are herein incorporatedby reference for at least material related to nucleic acid alignment. Itis understood that any of the methods typically can be used and that incertain instances the results of these various methods may differ, butthe skilled artisan understands if identity is found with at least oneof these methods, the sequences would be said to have the statedidentity, and be disclosed herein.

Protein modifications include amino acid sequence modifications.Modifications in amino acid sequence may arise naturally as allelicvariations (e.g., due to genetic polymorphism), may arise due toenvironmental influence (e.g., by exposure to ultraviolet light), or maybe produced by human intervention (e.g., by mutagenesis of cloned DNAsequences), such as induced point, deletion, insertion and substitutionmutants. These modifications can result in changes in the amino acidsequence, provide silent mutations, modify a restriction site, orprovide other specific mutations. Amino acid sequence modificationstypically fall into one or more of three classes: substitutional,insertional or deletional modifications. Insertions include amino and/orcarboxyl terminal fusions as well as intrasequence insertions of singleor multiple amino acid residues. Insertions ordinarily will be smallerinsertions than those of amino or carboxyl terminal fusions, forexample, on the order of one to four residues. Deletions arecharacterized by the removal of one or more amino acid residues from theprotein sequence. Typically, no more than about from 2 to 6 residues aredeleted at any one site within the protein molecule. Amino acidsubstitutions are typically of single residues, but can occur at anumber of different locations at once; insertions usually will be on theorder of about from 1 to 10 amino acid residues; and deletions willrange about from 1 to 30 residues. Deletions or insertions preferablyare made in adjacent pairs, i.e. a deletion of 2 residues or insertionof 2 residues. Substitutions, deletions, insertions or any combinationthereof may be combined to arrive at a final construct. The mutationsmust not place the sequence out of reading frame and preferably will notcreate complementary regions that could produce secondary mRNAstructure. Substitutional modifications are those in which at least oneresidue has been removed and a different residue inserted in its place.Such substitutions generally are made in accordance with the followingTable 2 and are referred to as conservative substitutions.

TABLE 2 Exemplary amino acid substitutions Amino Acid ExemplarySubstitutions Ala Ser, Gly, Cys Arg Lys, Gln, Met, Ile Asn Gln, His,Glu, Asp Asp Glu, Asn, Gln Cys Ser, Met, Thr Gln Asn, Lys, Glu, Asp GluAsp, Asn, Gln Gly Pro, Ala His Asn, Gln Ile Leu, Val, Met Leu Ile, Val,Met Lys Arg, Gln, Met, Ile Met Leu, Ile, Val Phe Met, Leu, Tyr, Trp, HisSer Thr, Met, Cys Thr Ser, Met, Val Trp Tyr, Phe Tyr Trp, Phe, His ValIle, Leu, Met

Modifications, including the specific amino acid substitutions, are madeby known methods. For example, modifications are made by site specificmutagenesis of nucleotides in the DNA encoding the polypeptide, therebyproducing DNA encoding the modification, and thereafter expressing theDNA in recombinant cell culture. Techniques for making substitutionmutations at predetermined sites in DNA having a known sequence are wellknown, for example M13 primer mutagenesis and PCR mutagenesis.

Modifications can be selected to optimize binding For example, affinitymaturation techniques can be used to alter binding of the scFv byintroducing random mutations inside the complementarity determiningregions (CDRs). Such random mutations can be introduced using a varietyof techniques, including radiation, chemical mutagens or error-pronePCR. Multiple rounds of mutation and selection can be performed using,for example, phage display.

The disclosure also relates to nucleic acids that encode the chimericpolypeptides described herein, and to the use of such nucleic acids toproduce the chimeric polypeptides and for therapeutic purposes. Forexample, the invention includes DNA and RNA molecules (e.g., mRNA,self-replicating RNA) that encode a chimeric polypeptide and to thetherapeutic use of such DNA and RNA molecules.

Exemplary Compositions

Exemplary fusion proteins of the invention combine the above describedelements in a variety of orientations. The orientations described inthis section are meant as examples and are not to be consideredlimiting.

In some embodiments, the fusion protein comprises a cytokine, a blockingmoiety and a half-life extension element. In some embodiments, thecytokine is positioned between the half-life extension element and theblocking moiety. In some embodiments, the cytokine is N-terminal to theblocking moiety and the half-life extension element. In some suchembodiments, the cytokine is proximal to the blocking moiety; in somesuch embodiments, the cytokine is proximal to the half-life extensionelement. At least one protease-cleavable linker must be included in allembodiments, such that the cytokine may be active upon cleavage. In someembodiments, the cytokine is C-terminal to the blocking moiety and thehalf-life extension element. Additional elements may be attached to oneanother by a cleavable linker, a non-cleavable linker, or by directfusion.

In some embodiments, the blocking domains used are capable of extendinghalf-life, and the cytokine is positioned between two such blockingdomains. In some embodiments, the cytokine is positioned between twoblocking domains, one of which is capable of extending half-life.

In some embodiments, two cytokines are included in the same construct.In some embodiments, the cytokines are connected to two blocking domainseach (three in total in one molecule), with a blocking domain betweenthe two cytokine domains. In some embodiments, one or more additionalhalf-life extension domains may be included to optimize pharmacokineticproperties. In some cases, it is beneficial to include two of the samecytokine to facilitate dimerization. An example of a cytokine that worksas a dimer is IFN□.

In some embodiments, three cytokines are included in the same construct.In some embodiments, the third cytokine may function to block the othertwo in place of a blocking domain between the two cytokines.

Preferred half-life extension elements for use in the fusion proteinsare human serum albumin (HSA), an antibody or antibody fragment (e.g.,scFV, dAb) which binds serum albumin, a human or humanized IgG, or afragment of any of the foregoing. In some preferred embodiments, theblocking moiety is human serum albumin (HSA), or an antibody or antibodyfragment which binds serum albumin, an antibody which binds the cytokineand prevents activation of binding or activation of the cytokinereceptor, another cytokine, or a fragment of any of the foregoing. Inpreferred embodiments comprising an additional targeting domain, thetargeting domain is an antibody which binds a cell surface protein whichis enriched on the surface of cancer cells, such as EpCAM, FOLR1, andFibronectin.

Methods of Treatment and Pharmaceutical Compositions

Further provided are methods of treating a subject with or at risk ofdeveloping an of a disease or disorder, such as proliferative disease, atumorous disease, an inflammatory disease, an immunological disorder, anautoimmune disease, an infectious disease, a viral disease, an allergicreaction, a parasitic reaction, or graft-versus-host disease. Themethods administering to a subject in need thereof an effective amountof a fusion protein as disclosed herein that is typically administeredas a pharmaceutical composition. In some embodiments, the method furthercomprises selecting a subject with or at risk of developing such adisease or disorder. The pharmaceutical composition preferably comprisesa blocked cytokine, fragment or mutein thereof that is activated at asite of inflammation or a tumor. In one embodiment, the chimericpolypeptide comprises a cytokine polypeptide, fragment or mutein thereofand a serum half-life extension element. In another embodiment, thechimeric polypeptide comprises a cytokine polypeptide, fragment ormutein thereof and a blocking moiety, e.g. a steric blockingpolypeptide, wherein the steric blocking polypeptide is capable ofsterically blocking the activity of the cytokine polypeptide, fragmentor mutein thereof. In another embodiment, the chimeric polypeptidecomprises a cytokine polypeptide, fragment or mutein thereof, a blockingmoiety, and a serum half-life extension element.

Inflammation is part of the complex biological response of body tissuesto harmful stimuli, such as pathogens, damaged cells, or irritants, andis a protective response involving immune cells, blood vessels, andmolecular mediators. The function of inflammation is to eliminate theinitial cause of cell injury, clear out necrotic cells and tissuesdamaged from the original insult and the inflammatory process, and toinitiate tissue repair. Inflammation can occur from infection, as asymptom or a disease, e.g., cancer, atherosclerosis, allergies,myopathies, HIV, obesity, or an autoimmune disease. An autoimmunedisease is a chronic condition arising from an abnormal immune responseto a self-antigen. Autoimmune diseases that may be treated with thepolypeptides disclosed herein include but are not limited to lupus,celiac disease, diabetes mellitus type 1, Graves disease, inflammatorybowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, andsystemic lupus erythematosus.

The pharmaceutical composition can comprise one or moreprotease-cleavable linker sequences. The linker sequence serves toprovide flexibility between polypeptides, such that each polypeptide iscapable of inhibiting the activity of the first polypeptide. The linkersequence can be located between any or all of the cytokine polypeptide,fragment or mutein thereof, the blocking moiety, and serum half-lifeextension element. Optionally, the composition comprises, two, three,four, or five linker sequences. The linker sequence, two, three, or fourlinker sequences can be the same or different linker sequences. In oneembodiment, the linker sequence comprises GGGGS (SEQ ID NO.: 449),GSGSGS (SEQ ID NO.: 450), or G(SGGG)₂SGGT (SEQ ID NO.: 451). In anotherembodiment, the linker comprises a protease-cleavable sequence selectedfrom group consisting of HSSKLQ (SEQ ID NO.: 25), GPLGVRG (SEQ ID NO.:445), IPVSLRSG (SEQ ID NO.: 446), VPLSLYSG (SEQ ID NO.: 447, andSGESPAYYTA (SEQ ID NO.: 448).

In some embodiments, the linker is cleaved by a protease selected fromthe group consisting of a kallikrein, thrombin, chymase,carboxypeptidase A, cathepsin G, an elastase, PR-3, granzyme M, acalpain, a matrix metalloproteinase (MMP), a plasminogen activator, acathepsin, a caspase, a tryptase, or a tumor cell surface protease.

Suitable linkers can be of different lengths, such as from 1 amino acid(e.g., Gly) to 20 amino acids, from 2 amino acids to 15 amino acids,from 3 amino acids to 12 amino acids, including 4 amino acids to 10amino acids, amino acids to 9 amino acids, 6 amino acids to 8 aminoacids, or 7 amino acids to 8 amino acids, and may be 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60amino acids.

Further provided are methods of treating a subject with or at risk ofdeveloping cancer. The methods comprise administering to the subject inneed thereof an effective amount of a chimeric polypeptide (a fusionprotein) as disclosed herein that is typically administered as apharmaceutical composition. In some embodiments, the method furthercomprises selecting a subject with or at risk of developing cancer. Thepharmaceutical composition preferably comprises a blocked cytokine,fragment or mutein thereof that is activated at a tumor site.Preferably, the tumor is a solid tumor. The cancer may be, but notlimited to, a colon cancer, a lung cancer, a melanoma, a sarcoma, arenal cell carcinoma, and a breast cancer.

The method can further involve the administration of one or moreadditional agents to treat cancer, such as chemotherapeutic agents(e.g., Adriamycin, Cerubidine, Bleomycin, Alkeran, Velban, Oncovin,Fluorouracil, Thiotepa, Methotrexate, Bisantrene, Noantrone, Thiguanine,Cytaribine, Procarabizine), immuno-oncology agents (e.g., anti-PD-L1,anti-CTLA4, anti-PD-1, anti-CD47, anti-GD2), cellular therapies (e.g,CAR-T, T-cell therapy), oncolytic viruses and the like.

Provided herein are pharmaceutical formulations or compositionscontaining the chimeric polypeptides and a pharmaceutically acceptablecarrier. The herein provided compositions are suitable foradministration in vitro or in vivo. By pharmaceutically acceptablecarrier is meant a material that is not biologically or otherwiseundesirable, i.e., the material is administered to a subject withoutcausing undesirable biological effects or interacting in a deleteriousmanner with the other components of the pharmaceutical formulation orcomposition in which it is contained. The carrier is selected tominimize degradation of the active ingredient and to minimize adverseside effects in the subject.

Suitable carriers and their formulations are described in Remington: TheScience and Practice of Pharmacy, 21^(st) Edition, David B. Troy, ed.,Lippicott Williams & Wilkins (2005). Typically, an appropriate amount ofa pharmaceutically-acceptable salt is used in the formulation to renderthe formulation isotonic, although the formulate can be hypertonic orhypotonic if desired. Examples of the pharmaceutically-acceptablecarriers include, but are not limited to, sterile water, saline,buffered solutions like Ringer's solution, and dextrose solution. The pHof the solution is generally about 5 to about 8 or from about 7 to 7.5.Other carriers include sustained release preparations such assemipermeable matrices of solid hydrophobic polymers containing theimmunogenic polypeptides. Matrices are in the form of shaped articles,e.g., films, liposomes, or microparticles. Certain carriers may be morepreferable depending upon, for instance, the route of administration andconcentration of composition being administered. Carriers are thosesuitable for administration of the chimeric polypeptides or nucleic acidsequences encoding the chimeric polypeptides to humans or othersubjects.

The pharmaceutical formulations or compositions are administered in anumber of ways depending on whether local or systemic treatment isdesired and on the area to be treated. The compositions are administeredvia any of several routes of administration, including topically,orally, parenterally, intravenously, intra-articularly,intraperitoneally, intramuscularly, subcutaneously, intracavity,transdermally, intrahepatically, intracranially,nebulization/inhalation, or by installation via bronchoscopy. In someembodiments, the compositions are administered locally(non-systemically), including intratumorally, intra-articularly,intrathecally, etc.

Preparations for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions, and emulsions. Examples ofnon-aqueous solvents are propylene glycol, polyethylene glycol,vegetable oils such as olive oil, and injectable organic esters such asethyl oleate. Aqueous carriers include water, alcoholic/aqueoussolutions, emulsions or suspensions, including saline and bufferedmedia. Parenteral vehicles include sodium chloride solution, Ringer'sdextrose, dextrose and sodium chloride, lactated Ringer's, or fixedoils. Intravenous vehicles include fluid and nutrient replenishers,electrolyte replenishers (such as those based on Ringer's dextrose), andthe like. Preservatives and other additives are optionally present suchas, for example, antimicrobials, anti-oxidants, chelating agents, andinert gases and the like.

Formulations for topical administration include ointments, lotions,creams, gels, drops, suppositories, sprays, liquids, and powders.Conventional pharmaceutical carriers, aqueous, powder, or oily bases,thickeners and the like are optionally necessary or desirable.

Compositions for oral administration include powders or granules,suspension or solutions in water or non-aqueous media, capsules,sachets, or tables. Thickeners, flavorings, diluents, emulsifiers,dispersing aids or binders are optionally desirable.

Optionally, the chimeric polypeptides or nucleic acid sequences encodingthe chimeric polypeptides are administered by a vector. There are anumber of compositions and methods which can be used to deliver thenucleic acid molecules and/or polypeptides to cells, either in vitro orin vivo via, for example, expression vectors. These methods andcompositions can largely be broken down into two classes: viral baseddelivery systems and non-viral based delivery systems. Such methods arewell known in the art and readily adaptable for use with thecompositions and methods described herein. Such compositions and methodscan be used to transfect or transduce cells in vitro or in vivo, forexample, to produce cell lines that express and preferably secrete theencoded chimeric polypeptide or to therapeutically deliver nucleic acidsto a subject. The components of the chimeric nucleic acids disclosedherein typically are operably linked in frame to encode a fusionprotein.

As used herein, plasmid or viral vectors are agents that transport thedisclosed nucleic acids into the cell without degradation and include apromoter yielding expression of the nucleic acid molecule and/orpolypeptide in the cells into which it is delivered. Viral vectors are,for example, Adenovirus, Adeno-associated virus, herpes virus, Vacciniavirus, Polio virus, Sindbis, and other RNA viruses, including theseviruses with the HIV backbone. Also preferred are any viral familieswhich share the properties of these viruses which make them suitable foruse as vectors. Retroviral vectors, in general are described by Coffinet al., Retroviruses, Cold Spring Harbor Laboratory Press (1997), whichis incorporated by reference herein for the vectors and methods ofmaking them. The construction of replication-defective adenoviruses hasbeen described (Berkner et al., J. Virol. 61:1213-20 (1987); Massie etal., Mol. Cell. Biol. 6:2872-83 (1986); Haj-Ahmad et al., J. Virol.57:267-74 (1986); Davidson et al., J. Virol. 61:1226-39 (1987); Zhang etal., BioTechniques 15:868-72 (1993)). The benefit and the use of theseviruses as vectors is that they are limited in the extent to which theycan spread to other cell types, since they can replicate within aninitial infected cell, but are unable to form new infectious viralparticles. Recombinant adenoviruses have been shown to achieve highefficiency after direct, in vivo delivery to airway epithelium,hepatocytes, vascular endothelium, CNS parenchyma, and a number of othertissue sites. Other useful systems include, for example, replicating andhost-restricted non-replicating vaccinia virus vectors.

The provided polypeptides and/or nucleic acid molecules can be deliveredvia virus like particles. Virus like particles (VLPs) consist of viralprotein(s) derived from the structural proteins of a virus. Methods formaking and using virus like particles are described in, for example,Garcea and Gissmann, Current Opinion in Biotechnology 15:513-7 (2004).

The provided polypeptides can be delivered by subviral dense bodies(DBs). DBs transport proteins into target cells by membrane fusion.Methods for making and using DBs are described in, for example,Pepperl-Klindworth et al., Gene Therapy 10:278-84 (2003).

The provided polypeptides can be delivered by tegument aggregates.Methods for making and using tegument aggregates are described inInternational Publication No. WO 2006/110728.

Non-viral based delivery methods, can include expression vectorscomprising nucleic acid molecules and nucleic acid sequences encodingpolypeptides, wherein the nucleic acids are operably linked to anexpression control sequence. Suitable vector backbones include, forexample, those routinely used in the art such as plasmids, artificialchromosomes, BACs, YACs, or PACs. Numerous vectors and expressionsystems are commercially available from such corporations as Novagen(Madison, Wis.), Clonetech (Pal Alto, Calif.), Stratagene (La Jolla,Calif.), and Invitrogen/Life Technologies (Carlsbad, Calif.). Vectorstypically contain one or more regulatory regions. Regulatory regionsinclude, without limitation, promoter sequences, enhancer sequences,response elements, protein recognition sites, inducible elements,protein binding sequences, 5′ and 3′ untranslated regions (UTRs),transcriptional start sites, termination sequences, polyadenylationsequences, and introns. Such vectors can also be used to make thechimeric polypeptides by expression is a suitable host cell, such as CHOcells.

Preferred promoters controlling transcription from vectors in mammalianhost cells may be obtained from various sources, for example, thegenomes of viruses such as polyoma, Simian Virus 40 (SV40), adenovirus,retroviruses, hepatitis B virus, and most preferably cytomegalovirus(CMV), or from heterologous mammalian promoters, e.g. β-actin promoteror EF1α promoter, or from hybrid or chimeric promoters (e.g., CMVpromoter fused to the β-actin promoter). Of course, promoters from thehost cell or related species are also useful herein.

Enhancer generally refers to a sequence of DNA that functions at nofixed distance from the transcription start site and can be either 5′ or3′ to the transcription unit. Furthermore, enhancers can be within anintron as well as within the coding sequence itself. They are usuallybetween 10 and 300 base pairs (bp) in length, and they function in cisEnhancers usually function to increase transcription from nearbypromoters Enhancers can also contain response elements that mediate theregulation of transcription. While many enhancer sequences are knownfrom mammalian genes (globin, elastase, albumin, fetoprotein, andinsulin), typically one will use an enhancer from a eukaryotic cellvirus for general expression. Preferred examples are the SV40 enhanceron the late side of the replication origin, the cytomegalovirus earlypromoter enhancer, the polyoma enhancer on the late side of thereplication origin, and adenovirus enhancers.

The promoter and/or the enhancer can be inducible (e.g. chemically orphysically regulated). A chemically regulated promoter and/or enhancercan, for example, be regulated by the presence of alcohol, tetracycline,a steroid, or a metal. A physically regulated promoter and/or enhancercan, for example, be regulated by environmental factors, such astemperature and light. Optionally, the promoter and/or enhancer regioncan act as a constitutive promoter and/or enhancer to maximize theexpression of the region of the transcription unit to be transcribed. Incertain vectors, the promoter and/or enhancer region can be active in acell type specific manner. Optionally, in certain vectors, the promoterand/or enhancer region can be active in all eukaryotic cells,independent of cell type. Preferred promoters of this type are the CMVpromoter, the SV40 promoter, the β-actin promoter, the EF1α promoter,and the retroviral long terminal repeat (LTR).

The vectors also can include, for example, origins of replication and/ormarkers. A marker gene can confer a selectable phenotype, e.g.,antibiotic resistance, on a cell. The marker product is used todetermine if the vector has been delivered to the cell and oncedelivered is being expressed. Examples of selectable markers formammalian cells are dihydrofolate reductase (DHFR), thymidine kinase,neomycin, neomycin analog G418, hygromycin, puromycin, and blasticidin.When such selectable markers are successfully transferred into amammalian host cell, the transformed mammalian host cell can survive ifplaced under selective pressure. Examples of other markers include, forexample, the E. coli lacZ gene, green fluorescent protein (GFP), andluciferase. In addition, an expression vector can include a tag sequencedesigned to facilitate manipulation or detection (e.g., purification orlocalization) of the expressed polypeptide. Tag sequences, such as GFP,glutathione S-transferase (GST), polyhistidine, c-myc, hemagglutinin, orFLAG™ tag (Kodak; New Haven, Conn.) sequences typically are expressed asa fusion with the encoded polypeptide. Such tags can be insertedanywhere within the polypeptide including at either the carboxyl oramino terminus.

As used herein, the terms peptide, polypeptide, or protein are usedbroadly to mean two or more amino acids linked by a peptide bond.Protein, peptide, and polypeptide are also used herein interchangeablyto refer to amino acid sequences. It should be recognized that the termpolypeptide is not used herein to suggest a particular size or number ofamino acids comprising the molecule and that a peptide of the inventioncan contain up to several amino acid residues or more. As usedthroughout, subject can be a vertebrate, more specifically a mammal(e.g. a human, horse, cat, dog, cow, pig, sheep, goat, mouse, rabbit,rat, and guinea pig), birds, reptiles, amphibians, fish, and any otheranimal. The term does not denote a particular age or sex. Thus, adultand newborn subjects, whether male or female, are intended to becovered. As used herein, patient or subject may be used interchangeablyand can refer to a subject with a disease or disorder (e.g. cancer). Theterm patient or subject includes human and veterinary subjects.

A subject at risk of developing a disease or disorder can be geneticallypredisposed to the disease or disorder, e.g., have a family history orhave a mutation in a gene that causes the disease or disorder, or showearly signs or symptoms of the disease or disorder. A subject currentlywith a disease or disorder has one or more than one symptom of thedisease or disorder and may have been diagnosed with the disease ordisorder.

The methods and agents as described herein are useful for bothprophylactic and therapeutic treatment. For prophylactic use, atherapeutically effective amount of the chimeric polypeptides orchimeric nucleic acid sequences encoding the chimeric polypeptidesdescribed herein are administered to a subject prior to onset (e.g.,before obvious signs of cancer or inflammation) or during early onset(e.g., upon initial signs and symptoms of cancer or inflammation).Prophylactic administration can occur for several days to years prior tothe manifestation of symptoms of cancer or inflammation. Prophylacticadministration can be used, for example, in the preventative treatmentof subjects diagnosed with a genetic predisposition to cancer.Therapeutic treatment involves administering to a subject atherapeutically effective amount of the chimeric polypeptides or nucleicacid sequences encoding the chimeric polypeptides described herein afterdiagnosis or development of cancer or inflammation (e.g., an autoimmunedisease). Prophylactic use may also apply when a patient is undergoing atreatment, e.g., a chemotherapy, in which inflammation is expected.

According to the methods taught herein, the subject is administered aneffective amount of the agent (e.g., a chimeric polypeptide). The termseffective amount and effective dosage are used interchangeably. The termeffective amount is defined as any amount necessary to produce a desiredphysiologic response. Effective amounts and schedules for administeringthe agent may be determined empirically, and making such determinationsis within the skill in the art. The dosage ranges for administration arethose large enough to produce the desired effect in which one or moresymptoms of the disease or disorder are affected (e.g., reduced ordelayed). The dosage should not be so large as to cause substantialadverse side effects, such as unwanted cross-reactions, anaphylacticreactions, and the like. Generally, the dosage will vary with the age,condition, sex, type of disease, the extent of the disease or disorder,route of administration, or whether other drugs are included in theregimen, and can be determined by one of skill in the art. The dosagecan be adjusted by the individual physician in the event of anycontraindications. Dosages can vary and can be administered in one ormore dose administrations daily, for one or several days. Guidance canbe found in the literature for appropriate dosages for given classes ofpharmaceutical products.

As used herein the terms treatment, treat, or treating refers to amethod of reducing the effects of a disease or condition or symptom ofthe disease or condition. Thus, in the disclosed method, treatment canrefer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%reduction in the severity of an established disease or condition orsymptom of the disease or condition. For example, a method for treatinga disease is considered to be a treatment if there is a 10% reduction inone or more symptoms of the disease in a subject as compared to acontrol. Thus, the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90%, 100%, or any percent reduction in between 10% and 100% ascompared to native or control levels. It is understood that treatmentdoes not necessarily refer to a cure or complete ablation of thedisease, condition, or symptoms of the disease or condition.

As used herein, the terms prevent, preventing, and prevention of adisease or disorder refers to an action, for example, administration ofthe chimeric polypeptide or nucleic acid sequence encoding the chimericpolypeptide, that occurs before or at about the same time a subjectbegins to show one or more symptoms of the disease or disorder, whichinhibits or delays onset or exacerbation of one or more symptoms of thedisease or disorder. As used herein, references to decreasing, reducing,or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90% or greater as compared to a control level. Such terms caninclude but do not necessarily include complete elimination.

IL-2 variants have been developed that are selective for IL2Rαβγrelative to IL2Rβγ (Shanafelt, A. B., et al., 2000, NatBiotechno1.18:1197-202; Cassell, D. J., et. al., 2002, Curr Pharm Des.,8:2171-83). These variants have amino acid substitutions which reducetheir affinity for IL2RB. Because IL-2 has undetectable affinity forIL2RG, these variants consequently have reduced affinity for the IL2Rβγreceptor complex and reduced ability to activate IL2Rβγ-expressingcells, but retain the ability to bind IL2RA and the ability to bind andactivate the IL2Rαβγ receptor complex.

One of these variants, IL2/N88R (Bay 50-4798), was clinically tested asa low-toxicity version of IL-2 as an immune system stimulator, based onthe hypothesis that IL2Rβγ-expressing NK cells are a major contributorto toxicity. Bay 50-4798 was shown to selectively stimulate theproliferation of activated T cells relative to NK cells, and wasevaluated in phase I/II clinical trials in cancer patients (Margolin,K., et. al., 2007, Clin Cancer Res., 13:3312-9) and HIV patients (Davey,R. T., et. al., 2008, J Interferon Cytokine Res., 28:89-100). Theseclinical trials showed that Bay 50-4798 was considerably safer and moretolerable than aldesleukin, and also showed that it increased the levelsof CD4+CD25+ T cells, a cell population enriched in Treg cells.Subsequent to these trials, research in the field more fully establishedthe identity of Treg cells and demonstrated that Treg cells selectivelyexpress IL2Rαβγ (reviewed in Malek, T. R., et al., 2010, Immunity,33:153-65).

In addition, mutants can be made that selectively alter the affinity forthe CD25 chain relative to native 11-2.

IL-2 can be engineered to produce mutants that bind the IL-2R complexgenerally or the IL-2Rα subunit specifically with an affinity thatdiffers from that of the corresponding wild-type IL-2 or of a presentlyavailable mutant (referred to as C125S, as the cysteine residue atposition 125 is replaced with a serine residue).

Accordingly, the present invention features mutant interleukin-2 (IL-2*)polypeptides that include an amino acid sequence that is at least 80%identical to wild-type IL-2 (e.g., 85, 87, 90, 95, 97, 98, or 99%identical) and that bind, as compared to WT IL-2, with higher to theIL-2 trimeric receptor relative to the dimeric IL-2 receptor. Typically,the muteins will also bind an IL-2 receptor a subunit (IL-2Rα) with anaffinity that is greater than the affinity with which wild type IL-2binds the IL-2Rα. The amino acid sequence within mutant IL-2polypeptides can vary from SEQ ID NO:1 (UniProtKB accession numberP60568) by virtue of containing (or only containing) one or more aminoacid substitutions, which may be considered conservative ornon-conservative substitutions. Non-naturally occurring amino acids canalso be incorporated. Alternatively, or in addition, the amino acidsequence can vary from SEQ ID NO:1 (which may be considered the“reference” sequence) by virtue of containing and addition and/ordeletion of one or more amino acid residues. More specifically, theamino acid sequence can differ from that of SEQ ID NO:1 by virtue of amutation at least one of the following positions of SEQ ID NO:1: 1, 4,8, 9, 10, 11, 13, 15, 26, 29, 30, 31, 35, 37, 46, 48, 49, 54, 61, 64,67, 68, 69, 71, 73, 74, 75, 76, 79, 88, 89, 90, 92, 99, 101, 103, 114,125, 128, or 133 (or combinations thereof). As noted, as few as one ofthese positions may be altered, as may two, three, four, five, six,seven, eight, nine, ten, or 11 or more (including up to all) of thepositions. For example, the amino acid sequence can differ from SEQ IDNO:1 at positions 69 and 74 and further at one or more of positions 30,35, and 128. The amino acid sequence can also differ from SEQ ID NO:2(as disclosed in U.S. Pat. No. 7,569,215, incorporated herein byreference) at one of the following sets of positions: (a) positions 64,69, and 74; (b) positions 69, 74, and 101; (c) positions 69, 74, and128; (d) positions 30, 69, 74, and 103; (e) positions 49, 69, 73, and76; (f) positions 69, 74, 101, and 133; (g) positions 30, 69, 74, and128; (h) positions 69, 74, 88, and 99; (i) positions 30, 69, 74, and128; (j) positions 9, 11, 35, 69, and 74; (k) positions 1, 46, 49, 61,69, and 79; (1) positions 48, 68, 71, 90, 103, and 114; (m) positions 4,10, 11, 69, 74, 88, and 133; (n) positions 15, 30 31, 35, 48, 69, 74,and 92; (0) positions 30, 68, 69, 71, 74, 75, 76, and 90; (p) positions30, 31, 37, 69, 73, 74, 79, and 128; (q) positions 26, 29, 30, 54, 67,69, 74, and 92; (r) positions 8, 13, 26, 30, 35, 37, 69, 74, and 92; and(s) positions 29, 31, 35, 37, 48, 69, 71, 74, 88, and 89. Aside frommutations at these positions, the amino acid sequence of the mutant IL-2polypeptide can otherwise be identical to SEQ ID NO:1. With respect tospecific substitutions, the amino acid sequence can differ from SEQ IDNO:1 by virtue of having one or more of the following mutations: A1T,S4P, K8R, K9T, T10A, Q11R, Q13R, E15K, N26D, N29S, N30S, N30D, N30T,Y31H, Y31C, K35R, T37A, T37R, M46L, K48E, K49R, K49E, K54R, E61D, K64R,E67G, E68D, V69A, N71T, N71A, N71R, A73V, Q74P, S75P, K76E, K76R, H79R,N88D, I89V, N90H, I92T, S99P, T101A, F103S, 1114V, I128T, I128A, T133A,or T133N. Our nomenclature is consistent with that of the scientificliterature, where the single letter code of the amino acid in thewild-type or reference sequence is followed by its position within thesequence and then by the single letter code of the amino acid with whichit is replaced. Thus, AlT designates a substitution of the alanineresidue a position 1 with threonine. Other mutant polypeptides withinthe scope of the invention include those that include a mutant of SEQ IDNO:2 having substitutions at V69 (e.g. A) and Q74 (e.g., P). Forexample, the amino acid sequence can include one of the following setsof mutations with respect to SEQ ID NO:2: (a) K64R, V69A, and Q74P; (b)V69A, Q74P, and T101A; (c) V69A, Q74P, and I128T; (d) N30D, V69A, Q74P,and F103S; (e) K49E, V69A, A73V, and K76E; (f) V69A, Q74P, T101A, andT133N; (g) N30S, V69A, Q74P, and I128A; (h) V69A, Q74P, N88D, and S99P;(i) N30S, V69A, Q74P, and I128T; (j) K9T, Q11R, K35R, V69A, and Q74P;(k) A1T, M46L, K49R, E61D, V69A, and H79R; (1) K48E, E68D, N71T, N90H,F103S, and I114V; (m) S4P, T10A, Q11R, V69A, Q74P, N88D, and T133A; (n)E15K, N30S Y31H, K35R, K48E, V69A, Q74P, and I92T; (o) N30S, E68D, V69A,N71A, Q74P, S75P, K76R, and N90H; (p) N30S, Y31C, T37A, V69A, A73V,Q74P, H79R, and I128T; (q) N26D, N29S, N30S, K54R, E67G, V69A, Q74P, andI92T; (r) K8R, Q13R, N26D, N30T, K35R, T37R, V69A, Q74P, and I92T; and(s) N29S, Y31H, K35R, T37A, K48E, V69A, N71R, Q74P, N88D, and I89V. SEQID NO:2 is disclosed in U.S. Pat. No. 7,569,215, which is incorporatedherein by reference as an exemplary IL-2 polypeptide sequence that canbe used in the invention.

As noted above, any of the mutant IL-2 polypeptides disclosed herein caninclude the sequences described; they can also be limited to thesequences described and otherwise identical to SEQ ID NO:1. Moreover,any of the mutant IL-2 polypeptides described herein can optionallyinclude a substitution of the cysteine residue at position 125 withanother residue (e.g., serine) and/or can optionally include a deletionof the alanine residue at position 1 of SEQ ID NO:1.

The mutant IL-2 polypeptides disclosed herein can bind to the IL-2Rαsubunit with a K_(d) of less than about 28 nM (e.g., less than about 25nM; less than about 5 nM; about 1 nM; less than about 500 pM; or lessthan about 100 pM). More specifically, a mutant IL-2 polypeptide canhave an affinity equilibrium constant less than 1.0 nM (e.g., about 0.8,0.6, 0.4, or 0.2 nM). Affinity can also be expressed as a relative rateof dissociation from an IL-2Rα subunit or from an IL-2 receptor complex(e.g., a complex expressed on the surface of a cell or otherwisemembrane bound). For example, the mutant IL-2 polypeptides candissociate from, e.g., IL-2Rα, at a decreased rate relative to awild-type polypeptide or to an IL-2 based therapeutic, e.g., IL-2*.Alternatively, affinity can be characterized as the time, or averagetime, an IL-2* polypeptide persists on, for example, the surface of acell expressing an IL-2R. For example, an IL-2*polypeptide can persiston the receptor for at least about 2, 5, 10, 50, 100, or 250 times (ormore).

Disclosed are materials, compositions, and components that can be usedfor, can be used in conjunction with, can be used in preparation for, orare products of the disclosed methods and compositions. These and othermaterials are disclosed herein, and it is understood that whencombinations, subsets, interactions, groups, etc. of these materials aredisclosed that while specific reference of each various individual andcollective combinations and permutations of these compounds may not beexplicitly disclosed, each is specifically contemplated and describedherein. For example, if a method is disclosed and discussed and a numberof modifications that can be made to a number of molecules including themethod are discussed, each and every combination and permutation of themethod, and the modifications that are possible are specificallycontemplated unless specifically indicated to the contrary. Likewise,any subset or combination of these is also specifically contemplated anddisclosed. This concept applies to all aspects of this disclosureincluding, but not limited to, steps in methods using the disclosedcompositions. Thus, if there are a variety of additional steps that canbe performed, it is understood that each of these additional steps canbe performed with any specific method steps or combination of methodsteps of the disclosed methods, and that each such combination or subsetof combinations is specifically contemplated and should be considereddisclosed.

Publications cited herein and the material for which they are cited arehereby specifically incorporated by reference in their entireties.

EXAMPLES

The following are examples of methods and compositions of the invention.It is understood that various other embodiments may be practiced, giventhe general description provided herein.

Example 1 Detection of IL-2, IL-2 Mutein, IL-2Rα and IL-2Rγ in FusionProteins by ELISA

IL-2 mutein is detected with a commercially available antibody, e.g.,the anti-IL-2 monoclonal (JES6-1A12) (BD Pharmingen; San Jose, Calif.).A positive control is used to show whether the monoclonal antibodyrecognizes the cytokine or mutein. Antibodies against IL-2Rα and IL-2Rγchain are also used. Wells of a 96-well plate are coated with anantibody (2.5 μg/ml) in PBS. Wells are blocked with 5% non-fat milk inPBS with 0.2% Tween®20 (PBS-M-Tw) and fusion proteins are added for 1-2hours at 37° C. After washing, an anti-IL-2 biotin-labeled antibody,e.g., JES5H4 (BD Pharmingen) is added and binding is detected usingStrepavidin HRP (Southern Biotechnology Associates; Birmingham, Ala.).The ELISA plate is developed by adding 50 μl O-phenylenediamine (OPD)(Sigma-Aldrich) in 0.1M Citrate pH 4.5 and 0.04% H_(b)O₂, stopped byadding 50 μl/well 2N H₂SO₄ and the absorbance was read at 490 nm.

Example 2 Protease Cleavage of Fusion Protein by MMP9 Protease

One of skill in the art would be familiar with methods of setting upprotein cleavage assay. 100 ug of protein in 1×PBS pH 7.4 were cleavedwith 1 μg active MMP9 (Sigma catalog #SAE0078-50 or Enzo catalogBML-SE360) and incubated at room temperature for up to 16 hours.Digested protein is subsequently used in functional assays or stored at−80° C. prior to testing. Extent of cleavage was monitored by SDS PAGEusing methods well known in the art. As shown in FIGS. 10, 13, 18A, 18B,24B, 24C, and 27A full cleavage of the fusion proteins by MMP9 proteaseis seen.

Example 3 CTLL-2 Assay

CTLL2 cells (ATCC) were plated in suspension at a concentration of500,000 cells/well in culture media with or without 40mg/ml human serumalbumin (HSA) and stimulated with a dilution series of recombinant hIL2or activatable hIL2 for 72 hours at 37° C. and 5% CO₂. Activity ofuncleaved and cleaved activatable hIL2 was tested. Cleaved activatablehIL2 was generated by incubation with active MMP9. Cell activity wasassessed using a CellTiter-Glo (Promega) luminescence-based cellviability assay. Results are shown in FIGS. 8, 9, and 25.

Example 4 Protease Cleavage of the IL-2/IL-2Rα/IL-2Rγ ChimericPolypeptide Results in Increased Accessibility to Antibodies andBiologically Active IL-2 Mutein

The IL-2 mutein fusion proteins are biochemically characterized beforeand after cleavage with a protease, e.g., PSA. Immunoblot analyses willshow that the fusion proteins can be cleaved by PSA and that there is anincrease in intensity of the predicted low molecular weight cleavageproduct of approximately 20 kDa reactive with an anti-IL-2 antibodyafter treatment of the samples with PSA. The degree of cleavage isdependent upon the amount of PSA as well as the time of incubation.Interestingly, when the fusion protein is analyzed before and after PSAtreatment by ELISA, it was found that the apparent amount of IL-2 isincreased after PSA cleavage. In this experiment, there is anapproximately 2 or 4-fold increase in the apparent amount of IL-2detected using this sandwich ELISA depending on the construct,suggesting that the antibody binding is partially hindered in the intactfusion protein. Aliquots of the same samples are also analyzed after PSAtreatment using the CTLL-2 cell line that requires IL-2 for growth andsurvival and the viability of cells can be ascertained using thecolorimetric MTT assay. In this assay, the more a supernatant can bediluted, the more biologically active IL-2 it contains, and there is anincrease in the amount of biologically active IL-2 after PSA cleavage.The amount of IL-2 mutein increase will suggest that after PSA cleavagethere is an increase in the predicted low molecular weight cleavagefragment of approximately 20 kDa reactive with an anti-IL-2 antibody, anincrease in antibody accessibility, and most importantly, an increase inthe amount of biologically active IL-2 mutein.

Example 5 In Vivo Delivery of a Protease Activated Fusion ProteinResults in Decreased Tumor Growth

The chimeric polypeptide is examined to determine if it could havebiological effects in vivo. For these experiments a system is used inwhich tumor cells injected intraperitoneally rapidly and preferentiallyattach and grow initially on the milky spots, a series of organizedimmune aggregates found on the omentum (Gerber et al., Am. J. Pathol.169:1739-52 (2006)). This system offers a convenient way to examine theeffects of fusion protein treatment on tumor growth since fusionproteins can be delivered intraperitoneally multiple times and tumorgrowth can be analyzed by examining the dissociated omental cells. Forthese experiments, the Colon 38 cell line, a rapidly growing tumor cellline that expresses both MMP2 and MMP9 in vitro, may be used. Theomental tissue normally expresses a relatively small amount of MMP2 andMMP9, but, when Colon 38 tumor is present on the omentum, MMP levelsincrease. Using this tumor model, the ability of IL-2 mutein fusionproteins to affect tumor growth is examined. Colon 38 cells are injectedintraperitoneally, allowed to attach and grow for 1 day, and thentreated daily with fusion protein interaperitoneally. At day 7, theanimals are sacrificed and the omenta examined for tumor growth usingflow cytometry and by a colony-forming assay.

Example 6 Construction of an Exemplary Activatable IL2 Protein TargetingCD20

Generation of an activatable IL2 Domain

An IL-2 polypeptide capable of binding to CD20 polypeptide present in atumor or on a tumor cell is produced as follows. A nucleic acid isproduced that contains nucleic acid sequences: (1) encoding an IFNγpolypeptide sequence and (2) one or more polypeptide linkers.Activatable interleukin plasmid constructs can have optional Flag, Hisor other affinity tags, and are electroporated into HEK293 or othersuitable human or mammalian cell lines and purified. Validation assaysinclude T cell activation assays using T cells responsive to IFNγstimulation in the presence of a protease.

Generation of a scFv CD20 Binding Domain

CD20 is one of the cell surface proteins present on B-lymphocytes. CD20antigen is found in normal and malignant pre-B and mature B lymphocytes,including those in over 90% of B-cell non-Hodgkin's lymphomas (NHL). Theantigen is absent in hematopoietic stem cells, activated B lymphocytes(plasma cells) and normal tissue. As such, several antibodies mostly ofmurine origin have been described: 1F5, 2B8/C2B8, 2H7, and 1H4.

Human or humanized anti-CD20 antibodies are therefore used to generatescFv sequences for CD20 binding domains of an activatable interleukinprotein. DNA sequences coding for human or humanized VL and VH domainsare obtained, and the codons for the constructs are, optionally,optimized for expression in cells from Homo sapiens. The order in whichthe VL and VH domains appear in the scFv is varied (i.e., VL-VH, orVH-VL orientation), and three copies of the “G4S” (SEQ ID NO.: 449) or“G₄S” (SEQ ID NO.: 449) subunit (G₄S)₃ (SEQ ID NO.: 452) connect thevariable domains to create the scFv domain. Anti-CD20 scFv plasmidconstructs can have optional Flag, His or other affinity tags, and areelectroporated into HEK293 or other suitable human or mammalian celllines and purified. Validation assays include binding analysis by FACS,kinetic analysis using Proteon, and staining of CD20-expressing cells.

Cloning of DNA Expression Constructs Encoding the Activatable IL2Protein

The activatable IL2 construct with protease cleavage site domains areused to construct an activatable interleukin protein in combination withan anti-CD20 scFv domain and a serum half-life extension element (e.g.,a HSA binding peptide or VH domain). For expression of an activatableinterleukin protein in CHO cells, coding sequences of all proteindomains are cloned into a mammalian expression vector system. In brief,gene sequences encoding the activatable interleukin domain, serumhalf-life extension element, and CD20 binding domain along with peptidelinkers L1 and L2 are separately synthesized and subcloned. Theresulting constructs are then ligated together in the order of CD20binding domain—L1—IL2 subunit 1—L2—protease cleavage domain—L3—IL2subunit 2—L4—anti-CD20 scFv—L5—serum half-life extension element toyield a final construct. All expression constructs are designed tocontain coding sequences for an N-terminal signal peptide and aC-terminal hexahistidine (6× His)-tag (SEQ ID NO. 354) to facilitateprotein secretion and purification, respectively.

Expression of Activatable IL2 Proteins in Stably Transfected CHO Cells

A CHO cell expression system (Flp-In®, Life Technologies), a derivativeof CHO-K1 Chinese Hamster ovary cells (ATCC, CCL-61) (Kao and Puck,Proc. Natl. Acad Sci USA 1968;60(4):1275-81), is used. Adherent cellsare subcultured according to standard cell culture protocols provided byLife Technologies.

For adaption to growth in suspension, cells are detached from tissueculture flasks and placed in serum-free medium. Suspension-adapted cellsare cryopreserved in medium with 10% DMSO.

Recombinant CHO cell lines stably expressing secreted activatableinterleukin proteins are generated by transfection of suspension-adaptedcells. During selection with the antibiotic Hygromycin B viable celldensities are measured twice a week, and cells are centrifuged andresuspended in fresh selection medium at a maximal density of 0.1×10⁶viable cells/mL. Cell pools stably expressing activatable interleukinproteins are recovered after 2-3 weeks of selection at which point cellsare transferred to standard culture medium in shake flasks. Expressionof recombinant secreted proteins is confirmed by performing protein gelelectrophoresis or flow cytometry. Stable cell pools are cryopreservedin DMSO containing medium.

Activatable IL2 proteins are produced in 10-day fed-batch cultures ofstably transfected CHO cell lines by secretion into the cell culturesupernatant. Cell culture supernatants are harvested after 10 days atculture viabilities of typically >75%. Samples are collected from theproduction cultures every other day and cell density and viability areassessed. On day of harvest, cell culture supernatants are cleared bycentrifugation and vacuum filtration before further use.

Protein expression titers and product integrity in cell culturesupernatants are analyzed by SDS-PAGE.

Purification of Activatable IL2 Proteins

Activatable IL2 proteins are purified from CHO cell culture supernatantsin a two-step procedure. The constructs are subjected to affinitychromatography in a first step followed by preparative size exclusionchromatography (SEC) on Superdex 200 in a second step. Samples arebuffer-exchanged and concentrated by ultrafiltration to a typicalconcentration of >1 mg/mL. Purity and homogeneity (typically >90%) offinal samples are assessed by SDS PAGE under reducing and non-reducingconditions, followed by immunoblotting using an anti-HSA or antiidiotype antibody as well as by analytical SEC, respectively. Purifiedproteins are stored at aliquots at −80° C. until use.

Example 7 Determination of Antigen Affinity by Flow Cytometry

The activatable interleukin proteins of Example 6 are tested for theirbinding affinities to human CD20⁺ cells and cynomolgus CD20⁺ cells.

CD20⁺ cells are incubated with 100 μL of serial dilutions of theactivatable interleukin proteins of Example 1 and at least one protease.After washing three times with FACS buffer the cells are incubated with0.1 mL of 10 μg/mL mouse monoclonal anti-idiotype antibody in the samebuffer for 45 min on ice. After a second washing cycle, the cells areincubated with 0.1 mL of 15 μg/mL FITC-conjugated goat anti-mouse IgGantibodies under the same conditions as before. As a control, cells areincubated with the anti-His IgG followed by the FITC-conjugated goatanti-mouse IgG antibodies without the activatable IL2 proteins. Thecells were then washed again and resuspended in 0.2 mL of FACS buffercontaining 2 μg/mL propidium iodide (PI) in order to exclude dead cells.The fluorescence of 1×10⁴ living cells is measured using aBeckman-Coulter FC500 MPL flow cytometer using the MXP software(Beckman-Coulter, Krefeld, Germany) or a Millipore Guava EasyCyte flowcytometer using the Incyte software (Merck Millipore, Schwalbach,Germany). Mean fluorescence intensities of the cell samples arecalculated using CXP software (Beckman-Coulter, Krefeld, Germany) orIncyte software (Merck Millipore, Schwalbach, Germany). Aftersubtracting the fluorescence intensity values of the cells stained withthe secondary and tertiary reagents alone the values are then used forcalculation of the K_(D) values with the equation for one-site binding(hyperbola) of the GraphPad Prism (version 6.00 for Windows, GraphPadSoftware, La Jolla Calif. USA).

CD20 binding and crossreactivity are assessed on the human CD20⁺ tumorcell lines. The K_(D) ratio of crossreactivity is calculated using theK_(D) values determined on the CHO cell lines expressing eitherrecombinant human or recombinant cynomolgus antigens.

Example 8 Cytotoxicity Assay

The activatable interleukin protein of Example 6 is evaluated in vitroon its mediation of immune response to CD20⁺ target cells.

Fluorescence labeled CD20⁺ REC-1 cells (a Mantle cell lymphoma cellline, ATCC CRL-3004) are incubated with isolated PBMC of random donorsor CB15 T-cells (standardized T-cell line) as effector cells in thepresence of the activatable IL2 protein of Example 5 and at least oneprotease. After incubation for 4 h at 37° C. in a humidified incubator,the release of the fluorescent dye from the target cells into thesupernatant is determined in a spectrofluorimeter. Target cellsincubated without the activatable IL2 protein of Example land targetcells totally lysed by the addition of saponin at the end of theincubation serve as negative and positive controls, respectively.

Based on the measured remaining living target cells, the percentage ofspecific cell lysis is calculated according to the following formula:[1-(number of living targets_((sample))/number of livingtargets_((spontaneous)))]×100%. Sigmoidal dose response curves and EC₅₀values are calculated by non-linear regression/4-parameter logistic fitusing the GraphPad Software. The lysis values obtained for a givenantibody concentration are used to calculate sigmoidal dose-responsecurves by 4 parameter logistic fit analysis using the Prism software.

Example 9 Pharmacokinetics of Activatable Interleukin Proteins

The activatable interleukin protein of Example 6 is evaluated forhalf-time elimination in animal studies.

The activatable IL2 protein is administered to cynomolgus monkeys as a0.5 mg/kg bolus injection into the saphenous vein. Another cynomolgusmonkey group receives a comparable IL2 construct in size, but lacking aserum half-life extension element. A third and fourth group receive anIL2 construct with serum half-life extension element and a cytokine withCD20 and serum half-life extension elements respectively, and bothcomparable in size to the activatable interleukin protein. Each testgroup consists of 5 monkeys. Serum samples are taken at indicated timepoints, serially diluted, and the concentration of the proteins isdetermined using a binding ELISA to CD20.

Pharmacokinetic analysis is performed using the test article plasmaconcentrations. Group mean plasma data for each test article conforms toa multi-exponential profile when plotted against the time post-dosing.The data are fit by a standard two-compartment model with bolus inputand first-order rate constants for distribution and elimination phases.The general equation for the best fit of the data for i.v.administration is: c(t)=Ae^(−αt)+Be^(−βt), where c(t) is the plasmaconcentration at time t, A and B are intercepts on the Y-axis, and α andβ are the apparent first-order rate constants for the distribution andelimination phases, respectively. The -phase is the initial phase of theclearance and reflects distribution of the protein into allextracellular fluid of the animal, whereas the second or β-phase portionof the decay curve represents true plasma clearance. Methods for fittingsuch equations are well known in the art. For example,A=DN(α−k21)/(α−β), B=D/V(β−k21)/(α−β), and α and β for α>β) are roots ofthe quadratic equation: r²+(k12+k21+k10)r+k21k10=0 using estimatedparameters of V=volume of distribution, k 10=elimination rate, k12=transfer rate from compartment 1 to compartment 2 and k21=transferrate from compartment 2 to compartment 1, and D=the administered dose.

Data analysis: Graphs of concentration versus time profiles are madeusing KaleidaGraph (KaleidaGraph™V. 3.09 Copyright 1986-1997. SynergySoftware. Reading, Pa.). Values reported as less than reportable (LTR)are not included in the PK analysis and are not represented graphically.Pharmacokinetic parameters are determined by compartmental analysisusing WinNonlin software (WinNonlin® Professional V. 3.1 WinNonlin™Copyright 1998-1999. Pharsight Corporation. Mountain View, Calif.).Pharmacokinetic parameters are computed as described in Ritschel W A andKearns G L, 1999, IN: Handbook Of Basic Pharmacokinetics IncludingClinical Applications, 5th edition, American Pharmaceutical Assoc.,Washington, D.C.

It is expected that the activatable interleukin protein of Example 5 hasimproved pharmacokinetic parameters such as an increase in eliminationhalf-time as compared to proteins lacking a serum half-life extensionelement.

Example 10 Xenograft Tumor Model

The activatable IL2 protein of Example 6 is evaluated in a xenograftmodel.

Female immune-deficient NOD/scid mice are sub-lethally irradiated (2 Gy)and subcutaneously inoculated with 4×10⁶ Ramos RA1 cells into the rightdorsal flank. When tumors reach 100 to 200 mm³, animals are allocatedinto 3 treatment groups. Groups 2 and 3 (8 animals each) areintraperitoneally injected with 1.5×10⁷ activated human T-cells. Threedays later, animals from Group 3 are subsequently treated with a totalof 9 intravenous doses of 50 μg activatable interleukin protein ofExample 1 (qd×9d). Groups 1 and 2 are only treated with vehicle. Bodyweight and tumor volume are determined for 30 days.

It is expected that animals treated with the activatable interleukinprotein of Example 5 have a statistically significant delay in tumorgrowth in comparison to the respective vehicle-treated control group.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

Example 11 Mouse IFNγ WEHI Cell Survival Assay

WEHI279 cells (ATCC) were plated in suspension at a concentration of25,000 cells/well in culture media with or without 1.5% human serumalbumin (HSA) and stimulated with a dilution series of recombinant mIFNγor inducible mIFNγ for 72 hours at 37° C. and 5% CO₂. Activity ofuncleaved and cleaved inducible mIFNγ was tested. Cleaved induciblemIFNg was generated by incubation with active MMP9. Cell survival wasassessed using a CellTiter-Glo (Promega) luminescence-based cellviability assay. The EC50 values for cleaved inducible mIFNg moleculeswere at least 100× more potent than un-cleaved inducible mIFNgmolecules. As shown in FIGS. 16A-16F, greater inducibility was seen inassays wherein the culture media contained human serum albumin.

Example 12 Mouse IFNγ B16 Reporter and Mouse IFNα/β B16 Reporter CellAssays

B16-Blue IFNγ cells (InvivoGen) were plated at a concentration of 75,000cells/well in culture media with or without 1.5% human serum albumin(HSA) and stimulated with a dilution series of recombinant mIFNγ orinducible mIFNγ for 24 hours at 37° C. and 5% CO₂. Activity of uncleavedand cleaved inducible mIFNγ was tested. Cleaved inducible mIFNγ wasgenerated by incubation with active MMP9. Supernatants were harvested,and SEAP activation was assessed by adding QUANTI-Blue Reagent(InvivoGen), incubating at 37° C. for 2 hours, and measuring absorbanceat 620 nm. Results are shown in FIGS. 17, 19, 22, 23, and 28. Thisexperiment was repeated with for IFNα fusion proteins using B16-BlueIFNα/β cells. The EC50 values for cleaved inducible mIFNα molecules wereat least 100× more potent than un-cleaved inducible mIFNα molecules.

Example 13 In Vivo Delivery of a Protease Activated Fusion ProteinResults in Decreased Tumor Growth

The chimeric polypeptide is examined to determine if it could havebiological effects in vivo. For these experiments a system is used inwhich tumor cells injected intraperitoneally rapidly and preferentiallyattach and grow initially on the milky spots, a series of organizedimmune aggregates found on the omentum (Gerber et al., Am. J. Pathol.169:1739-52 (2006)). This system offers a convenient way to examine theeffects of fusion protein treatment on tumor growth since fusionproteins can be delivered intraperitoneally multiple times and tumorgrowth can be analyzed by examining the dissociated omental cells. Forthese experiments, the Colon 38 cell line, a rapidly growing tumor cellline that expresses both MMP2 and MMP9 in vitro, may be used. Theomental tissue normally expresses a relatively small amount of MMP2 andMMP9, but, when Colon 38 tumor is present on the omentum, MMP levelsincrease. Using this tumor model, the ability of IFN fusion proteins toaffect tumor growth is examined. Colon 38 cells are injectedintraperitoneally, allowed to attach and grow for 1 day, and thentreated daily with fusion protein interaperitoneally. At day 7, theanimals are sacrificed and the omenta examined for tumor growth usingflow cytometry and by a colony-forming assay.

Example 13b The Chimeric Polypeptide was Examined to Determine itsBiological Effects In Vivo

The MC38 cell line, a rapidly growing colon adenocarcinoma cell linethat expresses MMP9 in vitro, was used. Using this tumor model, theability of IFNγ fusion proteins to affect tumor growth was examined.MC38 cells were injected subcutaneously, allowed to grow for 10-14 days,and then treated with fusion protein twice weekly intraperitoneally fora total of four doses, at the levels shown in FIGS. 21A-21D. As acomparator, wild-type mIFNγ was administered at the dose levelsindicated, twice daily for 2 weeks on a 5 day on/2 day off schedule (10total doses). Tumor growth and body weight were monitored approximatelytwice per week for two weeks.

Example 14 Construction of an Exemplary IFNγ Protein Targeting CD20Generation of an Activatable Cytokine Domain

An IFNγ polypeptide capable of binding to CD20 polypeptide present in atumor or on a tumor cell is produced as follows. A nucleic acid isproduced that contains nucleic acid sequences: (1) encoding an IFNγpolypeptide sequence and (2) one or more polypeptide linkers.Activatable IFNγ plasmid constructs can have optional Flag, His or otheraffinity tags, and are electroporated into HEK293 or other suitablehuman or mammalian cell lines and purified. Validation assays include Tcell activation assays using T cells responsive to IFNγ stimulation inthe presence of a protease.

Generation of a scFv CD20 Binding Domain

CD20 is one of the cell surface proteins present on B-lymphocytes. CD20antigen is found in normal and malignant pre-B and mature B lymphocytes,including those in over 90% of B-cell non-Hodgkin's lymphomas (NHL). Theantigen is absent in hematopoietic stem cells, activated B lymphocytes(plasma cells) and normal tissue. As such, several antibodies mostly ofmurine origin have been described: 1F5, 2B8/C2B8, 2H7, and 1H4.

Human or humanized anti-CD20 antibodies are therefore used to generatescFv sequences for CD20 binding domains of an activatable IFNγ protein.DNA sequences coding for human or humanized VL and VH domains areobtained, and the codons for the constructs are, optionally, optimizedfor expression in cells from Homo sapiens. The order in which the VL andVH domains appear in the scFv is varied (i.e., VL-VH, or VH-VLorientation), and three copies of the “G4S” (SEQ ID NO.: 449) or “G₄S”(SEQ ID NO.: 449) subunit (G₄S)₃ (SEQ ID NO.: 452) connect the variabledomains to create the scFv domain. Anti-CD20 scFv plasmid constructs canhave optional Flag, His or other affinity tags, and are electroporatedinto HEK293 or other suitable human or mammalian cell lines andpurified. Validation assays include binding analysis by FACS, kineticanalysis using Proteon, and staining of CD20-expressing cells.

Cloning of DNA Expression Constructs Encoding the Activatable IFNγProtein

The activatable IFNγ construct with protease cleavage site domains areused to construct an activatable IFNγ protein in combination with ananti-CD20 scFv domain and a serum half-life extension element (e.g., aHSA binding peptide or VH domain), with the domains organized as shownin FIG. 14. For expression of an activatable IFNγ protein in CHO cells,coding sequences of all protein domains are cloned into a mammalianexpression vector system. In brief, gene sequences encoding theactivatable IFNγ domain, serum half-life extension element, and CD20binding domain along with peptide linkers L1 and L2 are separatelysynthesized and subcloned. The resulting constructs are then ligatedtogether in the order of CD20 binding domain—L1—IFNγ subunit1—L2—protease cleavage domain—L3—IFNγ subunit2—L4—anti-CD20scFv—L5-serum half-life extension element to yield a final construct.All expression constructs are designed to contain coding sequences foran N-terminal signal peptide and a C-terminal hexahistidine (6× His)-tag(SEQ ID NO.: 354) to facilitate protein secretion and purification,respectively.

Expression of Activatable IFNγ Proteins in Stably Transfected CHO Cells

A CHO cell expression system (Flp-In®, Life Technologies), a derivativeof CHO-K1 Chinese Hamster ovary cells (ATCC, CCL-61) (Kao and Puck,Proc. Natl. Acad Sci USA 1968;60(4):1275-81), is used. Adherent cellsare subcultured according to standard cell culture protocols provided byLife Technologies.

For adaption to growth in suspension, cells are detached from tissueculture flasks and placed in serum-free medium. Suspension-adapted cellsare cryopreserved in medium with 10% DMSO.

Recombinant CHO cell lines stably expressing secreted activatable IFNγproteins are generated by transfection of suspension-adapted cells.During selection with the antibiotic Hygromycin B viable cell densitiesare measured twice a week, and cells are centrifuged and resuspended infresh selection medium at a maximal density of 0.1×10⁶ viable cells/mL.Cell pools stably expressing activatable IFNγ proteins are recoveredafter 2-3 weeks of selection at which point cells are transferred tostandard culture medium in shake flasks. Expression of recombinantsecreted proteins is confirmed by performing protein gel electrophoresisor flow cytometry. Stable cell pools are cryopreserved in DMSOcontaining medium.

Activatable IFNγ proteins are produced in 10-day fed-batch cultures ofstably transfected CHO cell lines by secretion into the cell culturesupernatant. Cell culture supernatants are harvested after 10 days atculture viabilities of typically >75%. Samples are collected from theproduction cultures every other day and cell density and viability areassessed. On day of harvest, cell culture supernatants are cleared bycentrifugation and vacuum filtration before further use.

Protein expression titers and product integrity in cell culturesupernatants are analyzed by SDS-PAGE.

Purification of Activatable IFNγ Proteins

Activatable IFNγ proteins are purified from CHO cell culturesupernatants in a two-step procedure. The constructs are subjected toaffinity chromatography in a first step followed by preparative sizeexclusion chromatography (SEC) on Superdex 200 in a second step. Samplesare buffer-exchanged and concentrated by ultrafiltration to a typicalconcentration of >1 mg/mL. Purity and homogeneity (typically >90%) offinal samples are assessed by SDS PAGE under reducing and non-reducingconditions, followed by immunoblotting using an anti-HSA or antiidiotype antibody as well as by analytical SEC, respectively. Purifiedproteins are stored at aliquots at −80° C. until use.

Example 15 Determination of Antigen Affinity by Flow Cytometry

The activatable IFNγ proteins of Example 1 are tested for their bindingaffinities to human CD20⁺ cells and cynomolgus CD20⁺ cells.

CD20⁺ cells are incubated with 100 μL of serial dilutions of theactivatable IFNγ proteins of Example 1 and at least one protease. Afterwashing three times with FACS buffer the cells are incubated with 0.1 mLof 10μg/mL mouse monoclonal anti-idiotype antibody in the same bufferfor 45 min on ice. After a second washing cycle, the cells are incubatedwith 0.1 mL of 15 μg/mL FITC-conjugated goat anti-mouse IgG antibodiesunder the same conditions as before. As a control, cells are incubatedwith the anti-His IgG followed by the FITC-conjugated goat anti-mouseIgG antibodies without the activatable IFNγ proteins. The cells werethen washed again and resuspended in 0.2 mL of FACS buffer containing 2μg/mL propidium iodide (PI) in order to exclude dead cells. Thefluorescence of 1×10⁴ living cells is measured using a Beckman-CoulterFC500 MPL flow cytometer using the MXP software (Beckman-Coulter,Krefeld, Germany) or a Millipore Guava EasyCyte flow cytometer using theIncyte software (Merck Millipore, Schwalbach, Germany). Meanfluorescence intensities of the cell samples are calculated using CXPsoftware (Beckman-Coulter, Krefeld, Germany) or Incyte software (MerckMillipore, Schwalbach, Germany). After subtracting the fluorescenceintensity values of the cells stained with the secondary and tertiaryreagents alone the values are then used for calculation of the K_(D)values with the equation for one-site binding (hyperbola) of theGraphPad Prism (version 6.00 for Windows, GraphPad Software, La JollaCalif. USA).

CD20 binding and crossreactivity are assessed on the human CD20⁺ tumorcell lines. The K_(D) ratio of crossreactivity is calculated using theK_(D) values determined on the CHO cell lines expressing eitherrecombinant human or recombinant cynomolgus antigens.

Example 16 Cytotoxicity Assay

The activatable IFNγ protein of Example 5 is evaluated in vitro on itsmediation of immune response to CD20⁺ target cells.

Fluorescence labeled CD20⁺ REC-1 cells (a Mantle cell lymphoma cellline, ATCC CRL-3004) are incubated with isolated PBMC of random donorsor CB15 T-cells (standardized T-cell line) as effector cells in thepresence of the activatable IFNγ protein of Example 5 and at least oneprotease. After incubation for 4 h at 37° C. in a humidified incubator,the release of the fluorescent dye from the target cells into thesupernatant is determined in a spectrofluorimeter. Target cellsincubated without the activatable IFNγ protein of Example 5 and targetcells totally lysed by the addition of saponin at the end of theincubation serve as negative and positive controls, respectively.

Based on the measured remaining living target cells, the percentage ofspecific cell lysis is calculated according to the following formula:[1-(number of living targets_((sample))/number of livingtargets_((spontaneous)))]×100%. Sigmoidal dose response curves and EC₅₀values are calculated by non-linear regression/4-parameter logistic fitusing the GraphPad Software. The lysis values obtained for a givenantibody concentration are used to calculate sigmoidal dose-responsecurves by 4 parameter logistic fit analysis using the Prism software.

Example 17 Pharmacokinetics of Activatable IFNγ Proteins

The activatable IFNγ protein of Example 5 is evaluated for half-timeelimination in animal studies.

The activatable IFNγ protein is administered to cynomolgus monkeys as a0.5 mg/kg bolus injection into the saphenous vein. Another cynomolgusmonkey group receives a comparable cytokine in size, but lacking a serumhalf-life extension element. A third and fourth group receive a cytokinewith serum half-life extension elements and a cytokine with CD20 andserum half-life extension elements respectively, and both comparable insize to the activatable IFNγ protein. Each test group consists of 5monkeys. Serum samples are taken at indicated time points, seriallydiluted, and the concentration of the proteins is determined using abinding ELISA to CD20.

Pharmacokinetic analysis is performed using the test article plasmaconcentrations. Group mean plasma data for each test article conforms toa multi-exponential profile when plotted against the time post-dosing.The data are fit by a standard two-compartment model with bolus inputand first-order rate constants for distribution and elimination phases.The general equation for the best fit of the data for i.v.administration is: c(t)=Ae^(αt)+Be^(−βt), where c(t) is the plasmaconcentration at time t, A and B are intercepts on the Y-axis, and α andβ are the apparent first-order rate constants for the distribution andelimination phases, respectively. The α-phase is the initial phase ofthe clearance and reflects distribution of the protein into allextracellular fluid of the animal, whereas the second or β-phase portionof the decay curve represents true plasma clearance. Methods for fittingsuch equations are well known in the art. For example,A=D/V(α−k21)/(α−β), B=D/V((β−k21)/(α−β), and α and β for α>β) are rootsof the quadratic equation: r²+(k12+k21+k10)r+k21k10=0 using estimatedparameters of V=volume of distribution, k 10=elimination rate, k12=transfer rate from compartment 1 to compartment 2 and k21=transferrate from compartment 2 to compartment 1, and D=the administered dose.

Data analysis: Graphs of concentration versus time profiles are madeusing KaleidaGraph (KaleidaGraph™ V. 3.09 Copyright 1986-1997. SynergySoftware. Reading, Pa.). Values reported as less than reportable (LTR)are not included in the PK analysis and are not represented graphically.Pharmacokinetic parameters are determined by compartmental analysisusing WinNonlin software (WinNonlin® Professional V. 3.1 WinNonlin™Copyright 1998-1999. Pharsight Corporation. Mountain View, Calif.).Pharmacokinetic parameters are computed as described in Ritschel W A andKearns G L, 1999, IN: Handbook Of Basic Pharmacokinetics IncludingClinical Applications, 5th edition, American Pharmaceutical Assoc.,Washington, D.C.

It is expected that the activatable IFNγ protein of Example 5 hasimproved pharmacokinetic parameters such as an increase in eliminationhalf-time as compared to proteins lacking a serum half-life extensionelement.

Example 18 Xenograft Tumor Model

The activatable IFNγ protein of Example 5 is evaluated in a xenograftmodel.

Female immune-deficient NOD/scid mice are sub-lethally irradiated (2 Gy)and subcutaneously inoculated with 4×10⁶ Ramos RA1 cells into the rightdorsal flank. When tumors reach 100 to 200 mm³, animals are allocatedinto 3 treatment groups. Groups 2 and 3 (8 animals each) areintraperitoneally injected with 1.5×10⁷ activated human T-cells. Threedays later, animals from Group 3 are subsequently treated with a totalof 9 intravenous doses of 50 μg activatable IFNγ protein of Example 5(qd×9d). Groups 1 and 2 are only treated with vehicle. Body weight andtumor volume are determined for 30 days.

It is expected that animals treated with the activatable IFNγ protein ofExample 5 have a statistically significant delay in tumor growth incomparison to the respective vehicle-treated control group.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

Example 19 HEK-Blue Assay

HEK-Blue IL12 cells (InvivoGen) were plated in suspension at aconcentration of 250,000 cells/well in culture media with or without40mg/ml human serum albumin (HSA) and stimulated with a dilution seriesof recombinant hIL12, chimeric IL12 (mouse p35/human p40) or activatablehIL12 for 24 hours at 37° C. and 5% CO₂. Activity of uncleaved andcleaved activatable hIL12 was tested. Cleaved inducible hIL12 wasgenerated by incubation with active MMP9. IL12 activity was assessed byquantification of Secreted Alkaline Phosphatase (SEAP) activity usingthe reagent QUANTI-Blue (InvivoGen), a colorimetric based assay. Resultsare shown in FIGS. 11, 12, 15, and 26.

HEK-Blue IL2 cells (InvivoGen) were plated in suspension at aconcentration of 50,000 cells/well in culture media with or without15-40 mg/ml human serum albumin (HSA) and stimulated with a dilutionseries of recombinant hIL2 or activatable hIL2 for 24 hours at 37□C and5% CO₂. Activity of uncleaved and cleaved activatable hIL2 was tested.Cleaved inducible hIL2 was generated by incubation with active MMP9.IL12 activity was assessed by quantification of Secreted AlkalinePhosphatase (SEAP) activity using the reagent QUANTI-Blue (InvivoGen), acolorimetric based assay. Results are shown in FIGS. 24A-24D.

Example 20 Splenocyte T-Blast Assay

T-Blasts were induced from murine splenocytes with a 6-day incubationwith PHA and a 24hr incubation with recombinant hIL12. Tblasts were thenplated in suspension at a concentration of 200,000 cells/well in culturemedia with or without 40 mg/ml human serum albumin (HSA) and stimulatedwith a dilution series of recombinant hIL12 or chimeric IL12 (mousep35/human p40) or mouse IL12 for 72 hours at 37° C. and 5% CO₂. Activityof uncleaved and cleaved IL12 fusion proteins was tested. Cleavedinducible hIL12 was generated by incubation with active MMP9. IL12activity was assessed by downstream quantification of IFNγ productionusing a mIFNγ alpha ELISA.

Example 21 In Vivo Delivery of a Protease Activated Fusion ProteinResults in Decreased Tumor Growth

The chimeric polypeptide is examined to determine if it could havebiological effects in vivo. For these experiments a system is used inwhich tumor cells injected intraperitoneally rapidly and preferentiallyattach and grow initially on the milky spots, a series of organizedimmune aggregates found on the omentum (Gerber et al., Am. J. Pathol.169:1739-52 (2006)). This system offers a convenient way to examine theeffects of fusion protein treatment on tumor growth since fusionproteins can be delivered intraperitoneally multiple times and tumorgrowth can be analyzed by examining the dissociated omental cells. Forthese experiments, the Colon 38 cell line, a rapidly growing tumor cellline that expresses both MMP2 and MMP9 in vitro, may be used. Theomental tissue normally expresses a relatively small amount of MMP2 andMMP9, but, when Colon 38 tumor is present on the omentum, MMP levelsincrease. Using this tumor model, the ability of IL-2 mutein fusionproteins to affect tumor growth is examined. Colon 38 cells are injectedintraperitoneally, allowed to attach and grow for 1 day, and thentreated daily with fusion protein interaperitoneally. At day 7, theanimals are sacrificed and the omenta examined for tumor growth usingflow cytometry and by a colony-forming assay.

Example 22 Construction of an Exemplary Activatable Interleukin ProteinTargeting CD20 Generation of an Activatable Interleukin Domain

The human IL-12p35 chain canonical sequence is Uniprot Accession No.P29459. The human IL-12p40 chain canonical sequence is Uniprot AccessionNo. P29460. IL-12p35 and IL-12p40 are cloned into an expressionconstruct. A protease cleavage site is included between the IL-12p35 andIL-12p40 domains. An IL-12 polypeptide capable of binding to CD20polypeptide present in a tumor or on a tumor cell is produced asfollows. A nucleic acid is produced that contains nucleic acidsequences: (1) encoding an IFNγ polypeptide sequence and (2) one or morepolypeptide linkers. Activatable interleukin plasmid constructs can haveoptional Flag, His or other affinity tags, and are electroporated intoHEK293 or other suitable human or mammalian cell lines and purified.Validation assays include T cell activation assays using T cellsresponsive to IL-12 stimulation in the presence of a protease.

Generation of a scFv CD20 Binding Domain

CD20 is one of the cell surface proteins present on B-lymphocytes. CD20antigen is found in normal and malignant pre-B and mature B lymphocytes,including those in over 90% of B-cell non-Hodgkin's lymphomas (NHL). Theantigen is absent in hematopoietic stem cells, activated B lymphocytes(plasma cells) and normal tissue. As such, several antibodies mostly ofmurine origin have been described: 1F5, 2B8/C2B8, 2H7, and 1H4.

Human or humanized anti-CD20 antibodies are therefore used to generatescFv sequences for CD20 binding domains of an activatable interleukinprotein. DNA sequences coding for human or humanized VL and VH domainsare obtained, and the codons for the constructs are, optionally,optimized for expression in cells from Homo sapiens. The order in whichthe VL and VH domains appear in the scFv is varied (i.e., VL-VH, orVH-VL orientation), and three copies of the “G4S” (SEQ ID NO.: 449) or“G₄S” (SEQ ID NO.: 449) subunit (G₄S)₃ (SEQ ID NO.: 452) connect thevariable domains to create the scFv domain. Anti-CD20 scFv plasmidconstructs can have optional Flag, His or other affinity tags, and areelectroporated into HEK293 or other suitable human or mammalian celllines and purified. Validation assays include binding analysis by FACS,kinetic analysis using Proteon, and staining of CD20-expressing cells.

Cloning of DNA Expression Constructs Encoding the ActivatableInterleukin Protein

The activatable interleukin construct with protease cleavage sitedomains are used to construct an activatable interleukin protein incombination with an anti-CD20 scFv domain and a serum half-lifeextension element (e.g., a HSA binding peptide or VH domain). Forexpression of an activatable interleukin protein in CHO cells, codingsequences of all protein domains are cloned into a mammalian expressionvector system. In brief, gene sequences encoding the activatableinterleukin domain, serum half-life extension element, and CD20 bindingdomain along with peptide linkers L1 and L2 are separately synthesizedand subcloned. The resulting constructs are then ligated together in theorder of CD20 binding domain—L1—IL-12p35—L2—protease cleavagedomain—L3—IL-12p40—L4—anti-CD20 scFv—L5—serum half-life extensionelement to yield a final construct. All expression constructs aredesigned to contain coding sequences for an N-terminal signal peptideand a C-terminal hexahistidine (6× His)-tag (SEQ ID NO.: 354) tofacilitate protein secretion and purification, respectively.

Expression of Activatable Interleukin Proteins in Stably Transfected CHOCells

A CHO cell expression system (Flp-In®, Life Technologies), a derivativeof CHO-K1 Chinese Hamster ovary cells (ATCC, CCL-61) (Kao and Puck,Proc. Natl. Acad Sci USA 1968;60(4):1275-81), is used. Adherent cellsare subcultured according to standard cell culture protocols provided byLife Technologies.

For adaption to growth in suspension, cells are detached from tissueculture flasks and placed in serum-free medium. Suspension-adapted cellsare cryopreserved in medium with 10% DMSO.

Recombinant CHO cell lines stably expressing secreted activatableinterleukin proteins are generated by transfection of suspension-adaptedcells. During selection with the antibiotic Hygromycin B viable celldensities are measured twice a week, and cells are centrifuged andresuspended in fresh selection medium at a maximal density of 0.1×10⁶viable cells/mL. Cell pools stably expressing activatable interleukinproteins are recovered after 2-3 weeks of selection at which point cellsare transferred to standard culture medium in shake flasks. Expressionof recombinant secreted proteins is confirmed by performing protein gelelectrophoresis or flow cytometry. Stable cell pools are cryopreservedin DMSO containing medium.

Activatable interleukin proteins are produced in 10-day fed-batchcultures of stably transfected CHO cell lines by secretion into the cellculture supernatant. Cell culture supernatants are harvested after 10days at culture viabilities of typically >75%. Samples are collectedfrom the production cultures every other day and cell density andviability are assessed. On day of harvest, cell culture supernatants arecleared by centrifugation and vacuum filtration before further use.

Protein expression titers and product integrity in cell culturesupernatants are analyzed by SDS-PAGE.

Purification of Activatable Interleukin Proteins

Activatable interleukin proteins are purified from CHO cell culturesupernatants in a two-step procedure. The constructs are subjected toaffinity chromatography in a first step followed by preparative sizeexclusion chromatography (SEC) on Superdex 200 in a second step. Samplesare buffer-exchanged and concentrated by ultrafiltration to a typicalconcentration of >1 mg/mL. Purity and homogeneity (typically >90%) offinal samples are assessed by SDS PAGE under reducing and non-reducingconditions, followed by immunoblotting using an anti-HSA or antiidiotype antibody as well as by analytical SEC, respectively. Purifiedproteins are stored at aliquots at -80° C. until use.

Example 23 Determination of Antigen Affinity by Flow Cytometry

The activatable interleukin proteins of Example 5 are tested for theirbinding affinities to human CD20⁺ cells and cynomolgus CD20⁺ cells.

CD20⁺ cells are incubated with 100 μL of serial dilutions of theactivatable interleukin proteins of Example 5 and at least one protease.After washing three times with FACS buffer the cells are incubated with0.1 mL of 10 μg/mL mouse monoclonal anti-idiotype antibody in the samebuffer for 45 min on ice. After a second washing cycle, the cells areincubated with 0.1 mL of 15 μg/mL FITC-conjugated goat anti-mouse IgGantibodies under the same conditions as before. As a control, cells areincubated with the anti-His IgG followed by the FITC-conjugated goatanti-mouse IgG antibodies without the activatable interleukin proteins.The cells were then washed again and resuspended in 0.2 mL of FACSbuffer containing 2 μg/mL propidium iodide (PI) in order to exclude deadcells. The fluorescence of 1×10⁴ living cells is measured using aBeckman-Coulter FC500 MPL flow cytometer using the MXP software(Beckman-Coulter, Krefeld, Germany) or a Millipore Guava EasyCyte flowcytometer using the Incyte software (Merck Millipore, Schwalbach,Germany). Mean fluorescence intensities of the cell samples arecalculated using CXP software (Beckman-Coulter, Krefeld, Germany) orIncyte software (Merck Millipore, Schwalbach, Germany). Aftersubtracting the fluorescence intensity values of the cells stained withthe secondary and tertiary reagents alone the values are then used forcalculation of the K_(D) values with the equation for one-site binding(hyperbola) of the GraphPad Prism (version 6.00 for Windows, GraphPadSoftware, La Jolla Calif. USA).

CD20 binding and crossreactivity are assessed on the human CD20⁺ tumorcell lines. The K_(D) ratio of crossreactivity is calculated using theK_(D) values determined on the CHO cell lines expressing eitherrecombinant human or recombinant cynomolgus antigens.

Example 24 Cytotoxicity Assay

The activatable interleukin protein of Example 5 is evaluated in vitroon its mediation of immune response to CD20⁺ target cells.

Fluorescence labeled CD20⁺ REC-1 cells (a Mantle cell lymphoma cellline, ATCC CRL-3004) are incubated with isolated PBMC of random donorsor CB15 T-cells (standardized T-cell line) as effector cells in thepresence of the activatable interleukin protein of Example 5 and atleast one protease. After incubation for 4 h at 37° C. in a humidifiedincubator, the release of the fluorescent dye from the target cells intothe supernatant is determined in a spectrofluorimeter. Target cellsincubated without the activatable interleukin protein of Example Sandtarget cells totally lysed by the addition of saponin at the end of theincubation serve as negative and positive controls, respectively.

Based on the measured remaining living target cells, the percentage ofspecific cell lysis is calculated according to the following formula:[1-(number of living targets_((sample))/number of livingtargets_((spontaneous)))]×100%. Sigmoidal dose response curves and EC₅₀values are calculated by non-linear regression/4-parameter logistic fitusing the GraphPad Software. The lysis values obtained for a givenantibody concentration are used to calculate sigmoidal dose-responsecurves by 4 parameter logistic fit analysis using the Prism software.

Example 25 Pharmacokinetics of Activatable Interleukin Proteins

The activatable interleukin protein of Example 5 is evaluated forhalf-time elimination in animal studies.

The activatable interleukin protein is administered to cynomolgusmonkeys as a 0.5 mg/kg bolus injection into the saphenous vein. Anothercynomolgus monkey group receives a comparable cytokine in size, butlacking a serum half-life extension element. A third and fourth groupreceive a cytokine with serum half-life extension elements and acytokine with CD20 and serum half-life extension elements respectively,and both comparable in size to the activatable interleukin protein. Eachtest group consists of 5 monkeys. Serum samples are taken at indicatedtime points, serially diluted, and the concentration of the proteins isdetermined using a binding ELISA to CD20.

Pharmacokinetic analysis is performed using the test article plasmaconcentrations. Group mean plasma data for each test article conforms toa multi-exponential profile when plotted against the time post-dosing.The data are fit by a standard two-compartment model with bolus inputand first-order rate constants for distribution and elimination phases.The general equation for the best fit of the data for i.v.administration is: c(t)=Ae^(−αt)+Be^(−βt), where c(t) is the plasmaconcentration at time t, A and B are intercepts on the Y-axis, and + andβ are the apparent first-order rate constants for the distribution andelimination phases, respectively. The α-phase is the initial phase ofthe clearance and reflects distribution of the protein into allextracellular fluid of the animal, whereas the second or β-phase portionof the decay curve represents true plasma clearance. Methods for fittingsuch equations are well known in the art. For example,A=D/V(α−k21)/(α−β), B=D/V((β−k21)/(α−β), and α and β (for α>β) are rootsof the quadratic equation: r²+(k12+k21+k10)r+k21k10=0 using estimatedparameters of V=volume of distribution, k 10=elimination rate, k12=transfer rate from compartment 1 to compartment 2 and k21=transferrate from compartment 2 to compartment 1, and D=the administered dose.

Data analysis: Graphs of concentration versus time profiles are madeusing KaleidaGraph (KaleidaGraph™ V. 3.09 Copyright 1986-1997. SynergySoftware. Reading, Pa.). Values reported as less than reportable (LTR)are not included in the PK analysis and are not represented graphically.Pharmacokinetic parameters are determined by compartmental analysisusing WinNonlin software (WinNonlin® Professional V. 3.1 WinNonlin™Copyright 1998-1999. Pharsight Corporation. Mountain View, Calif.).Pharmacokinetic parameters are computed as described in Ritschel W A andKearns G L, 1999, IN: Handbook Of Basic Pharmacokinetics IncludingClinical Applications, 5th edition, American Pharmaceutical Assoc.,Washington, D.C.

It is expected that the activatable interleukin protein of Example 5 hasimproved pharmacokinetic parameters such as an increase in eliminationhalf-time as compared to proteins lacking a serum half-life extensionelement.

Example 26 Xenograft Tumor Model

The activatable interleukin protein of Example 5 is evaluated in axenograft model.

Female immune-deficient NOD/scid mice are sub-lethally irradiated (2 Gy)and subcutaneously inoculated with 4×10⁶ Ramos RA1 cells into the rightdorsal flank. When tumors reach 100 to 200 mm³, animals are allocatedinto 3 treatment groups. Groups 2 and 3 (8 animals each) areintraperitoneally injected with 1.5×10⁷ activated human T-cells. Threedays later, animals from Group 3 are subsequently treated with a totalof 9 intravenous doses of 50 μg activatable interleukin protein ofExample 5 (qd×9d). Groups 1 and 2 are only treated with vehicle. Bodyweight and tumor volume are determined for 30 days.

It is expected that animals treated with the activatable interleukinprotein of Example 5 have a statistically significant delay in tumorgrowth in comparison to the respective vehicle-treated control group.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

Example 27 MC38 Experiments

The MC38 cell line, a rapidly growing colon adenocarcinoma cell linethat expresses MMP9 in vitro, was used. Using this tumor model, theability of fusion proteins to affect tumor growth was examined.

Example 27a MC38 IL-2POC Agents and Treatment:

Formulation Gr. N Agent dose Route Schedule  1^(#) 10 Vehicle — ip biwkx 3 2 7 ACP16 700 μg/animal ip biwk x 3 3 7 ACP16 230 μg/animal ip biwkx 3 4 7 ACP16 70 μg/animal ip biwk x 3 5 7 ACP16 55 ug/animal ip biwk x3 6 7 ACP16 17 μg/animal ip biwk x 3 7 7 ACP132 361 μg/animal ip biwk x3 8 7 ACP132 119 μg/animal ip biwk x 3 9 7 ACP132 36 μg/animal ip biwk x3 10  7 ACP132 28 μg/animal ip biwk x 3 11  7 ACP132 9 μg/animal ip biwkx 3 12  7 ACP21 540 μg/animal ip biwk x 3 13  7 ACP21 177 μg/animal ipbiwk x 3 14  7 ACP21 54 μg/animal ip biwk x 3 15  7 ACP21 42 μg/animalip biwk x 3 16  7 ACP21 13 μg/animal ip biwk x 3 # −ControlGroup

Procedures:

Mice were anaesthetized with isoflurane for implant of cells to reducethe ulcerations. 308 CR female C57BL/6 mice were set up with 5×10⁵ MC38tumor cells in 0% Matrigel sc in flank. Cell Injection Volume was 0.1mL/mouse. Mouse age at start date was 8 to 12 weeks. Pair matches wereperformed when tumors reach an average size of 100-150 mm³ and begintreatment. Body weights were taken at initiation and then biweekly tothe end. Caliper measurements were taken biweekly to the end. Anyadverse reactions were to be reported immediately. Any individual animalwith a single observation of >than 30% body weight loss or threeconsecutive measurements of >25% body weight loss was euthanized. Anygroup with a mean body weight loss of >20% or >10% mortality stoppeddosing; the group was not euthanized and recovery is allowed. Within agroup with >20% weight loss, individuals hitting the individual bodyweight loss endpoint were euthanized. If the group treatment relatedbody weight loss is recovered to within 10% of the original weights,dosing resumed at a lower dose or less frequent dosing schedule.Exceptions to non-treatment body weight % recovery were allowed on acase-by-case basis. Endpoint was tumor growth delay (TGD). Animals weremonitored individually. The endpoint of the experiment was a tumorvolume of 1500 mm³ or 45 days, whichever comes first. Responders werefollowed longer. When the endpoint was reached, the animals are to beeuthanized.

Results are shown in FIG. 35.

Example 27b MC38 IL-2 POC. Treatment with ACP16, ACP124 and ACP130Agents and Treatment:

Formulation Gr. N Agent dose Route Schedule  1^(#) 12 Vehicle — ip biwkx 2 2 8 ACP16 4.4 μg/animal ip biwk x 2 3 8 ACP16 17 μg/animal ip biwk x2 4 8 ACP16 70 μg/animal ip biwk x 2 5 8 ACP16 232 μg/animal ip biwk x 26 8 ACP130 19 μg/animal ip biwk x 2 7 8 ACP130 45 μg/animal ip biwk x 28 8 ACP130 180 μg/animal ip biwk x 2 9 8 ACP130 600 μg/animal ip biwk x1 12  8 ACP124 17 μg/animal ip biwk x 2 13  8 ACP124 70 μg/animal ipbiwk x 2 14  8 ACP124 230 μg/animal ip biwk x 2 15  8 ACP124 700μg/animal ip biwk x 2 16  8 IL-2- 12 μg/animal ip bid x 5 then 2-daypause then WTI bid x 5 then 2-day pause 17  8 IL-2- 36 μg/animal ip bidx 5 then 2-day pause then WTI bid x 5 then 2-day pause # −Control Group

Procedures:

Mice were anaesthetized with isoflurane for implant of cells to reducethe ulcerations. 308 CR female C57BL/6 mice were set up with 5×10⁵ MC38tumor cells in 0% Matrigel sc in flank. Cell Injection Volume was 0.1mL/mouse. Mouse age at start date was 8 to 12 weeks.Pair matches wereperformed when tumors reach an average size of 100-150 mm³ and begintreatment. Body weights were taken at initiation and then biweekly tothe end. Caliper measurements were taken biweekly to the end. Anyadverse reactions were to be reported immediately. Any individual animalwith a single observation of >than 30% body weight loss or threeconsecutive measurements of >25% body weight loss was euthanized. Anygroup with a mean body weight loss of >20% or >10% mortality stoppeddosing; the group was not euthanized and recovery is allowed. Within agroup with >20% weight loss, individuals hitting the individual bodyweight loss endpoint were euthanized. If the group treatment relatedbody weight loss is recovered to within 10% of the original weights,dosing resumed at a lower dose or less frequent dosing schedule.Exceptions to non-treatment body weight % recovery were allowed on acase-by-case basis. Endpoint was tumor growth delay (TGD). Animals weremonitored individually. The endpoint of the experiment was a tumorvolume of 1500 mm³ or 45 days, whichever comes first. Responders werefollowed longer. When the endpoint was reached, the animals are to beeuthanized.

Results are shown in FIGS. 31A-31C and FIGS. 32B-32C. Survival curvesare shown in FIGS. 34A-34D.

Example 27c MC38 IFNa and IL-12 Agents and Treatment:

Formulation Gr. N Agent dose Route Schedule  1^(#) 12 Vehicle — ip biwkx 3 2 8 ACP11 17.5 μg/animal ip biwk x 3 3 8 ACP11 175 μg/animal ip biwkx 3 4 8 ACP11 525 μg/animal ip biwk x 3 5 8 ACP31 33 μg/animal ip biwk x3 6 8 ACP31 110 μg/animal ip biwk x 3 7 8 ACP31 330 μg/animal ip biwk x3 8 8 ACP131 1 μg/animal ip bid x 5 then 2-day pause then bid x 5 then2- day pause 9 8 ACP131 10 μg/animal ip bid x 5 then 2-day pause thenbid x 5 then 2- day pause 10  8 ACP131 30 μg/animal ip bid x 5 then2-day pause then bid x 5 then 2- day pause 11  8 mIFNa1-WTI 1 μg/animalip bid x 5 then 2-day pause then bid x 5 then 2- day pause 12  8mIFNa1-WTI 10 μg/animal ip bid x 5 then 2-day pause then bid x 5 then 2-day pause 13  8 IL-12-HM-WTI 2 μg/animal ip bid x 5 then 2-day pausethen bid x 5 then 2- day pause 14  8 IL-12-HM-WTI 10 μg/animal ip bid x5 then 2-day pause then bid x 5 then 2- day pause 15  8 ACP131 5μg/animal itu bid x 5 then 2-day pause then bid x 5 then 2- day pause #−Control Group

Procedures:

Mice were anaesthetized with isoflurane for implant of cells to reducethe ulcerations. 308 CR female C57BL/6 mice were set up with 5×10⁵ MC38tumor cells in 0% Matrigel sc in flank. Cell Injection Volume was 0.1mL/mouse. Mouse age at start date was 8 to 12 weeks.Pair matches wereperformed when tumors reach an average size of 100-150 mm³ and begintreatment. Body weights were taken at initiation and then biweekly tothe end. Caliper measurements were taken biweekly to the end. Anyadverse reactions were to be reported immediately. Any individual animalwith a single observation of >than 30% body weight loss or threeconsecutive measurements of >25% body weight loss was euthanized. Anygroup with a mean body weight loss of >20% or >10% mortality stoppeddosing; the group was not euthanized and recovery is allowed. Within agroup with >20% weight loss, individuals hitting the individual bodyweight loss endpoint were euthanized. If the group treatment relatedbody weight loss is recovered to within 10% of the original weights,dosing resumed at a lower dose or less frequent dosing schedule.Exceptions to non-treatment body weight % recovery were allowed on acase-by-case basis. Endpoint was tumor growth delay (TGD). Animals weremonitored individually. The endpoint of the experiment was a tumorvolume of 1500 mm³ or 45 days, whichever comes first. Responders werefollowed longer. When the endpoint was reached, the animals are to beeuthanized. Results are show in in FIGS. 29A-29B, and 30A-30F.

Example 27d Treatment with ACP16, ACP132, and ACP21 Agents andTreatment:

Formulation Gr. N Agent dose Route Schedule  1^(#) 10 Vehicle — ip biwkx 2 2 7 ACP16 17 μg/animal ip biwk x 2 3 7 ACP16 55 μg/animal ip biwk x2 4 7 ACP16 70 μg/animal ip biwk x 2 5 7 ACP16 230 μg/animal ip biwk x 26 7 ACP132 9 μg/animal ip biwk x 2 7 7 ACP132 28 μg/animal ip biwk x 1 87 ACP132 36 μg/animal ip biwk x 1 9 7 ACP132 119 μg/animal ip biwk x 110  7 ACP21 13 μg/animal ip biwk x 2 11  7 ACP21 42 μg/animal ip biwk x2 12  7 ACP21 54 μg/animal ip biwk x 2 13  7 ACP21 177 μg/animal ip biwkx 2

Procedures:

Mice were anaesthetized with isoflurane for implant of cells to reducethe ulcerations. CR female C57BL/6 mice were set up with 5×10⁵ MC38tumor cells in 0% Matrigel sc in flank. Cell Injection Volume was 0.1mL/mouse. Mouse age at start date was 8 to 12 weeks.Pair matches wereperformed when tumors reach an average size of 100-150 mm³ and begintreatment. ACP16 was dosed at 17, 55, 70, or 230 μg/animal; ACP132 wasdosed at 9, 28, 36, or 119 ug/animal; ACP21 was dosed at 13, 42, 54, or177 μg/animal. Body weights were taken at initiation and then biweeklyto the end. Caliper measurements were taken biweekly to the end. Anyadverse reactions were to be reported immediately. Any individual animalwith a single observation of >than 30% body weight loss or threeconsecutive measurements of >25% body weight loss was euthanized. Anygroup with a mean body weight loss of >20% or >10% mortality stoppeddosing; the group was not euthanized and recovery is allowed. Within agroup with >20% weight loss, individuals hitting the individual bodyweight loss endpoint were euthanized. If the group treatment relatedbody weight loss is recovered to within 10% of the original weights,dosing resumed at a lower dose or less frequent dosing schedule.Exceptions to non-treatment body weight % recovery were allowed on acase-by-case basis. Endpoint was tumor growth delay (TGD). Animals weremonitored individually. The endpoint of the experiment was a tumorvolume of 1500 mm³ or 45 days, whichever comes first. Responders werefollowed longer. When the endpoint was reached, the animals are to beeuthanized. Results are shown in FIG. 35.

Example 27e MC38 Rechallenge

Cured mice (ACP16-treated) from Example 27b were rechallenged with tumorimplantation to determine whether anti-tumor memory had been establishedfrom the initial treatments.

Agents and Treatment:

Formulation Gr. N Agent dose Route Schedule  1^(#) 33 No — — — Treatment2 7 ACP16 70 μg/animal ip (ACP16 biwkx2) 3 8 ACP16 232 μg/animal ip(ACP16 biwkx2) 5 5 IL-2-WTI 12 μg/animal ip (IL-2-WTI bid x 5 then 2-daypause then bid x 5 then 2-day pause) 6 7 IL-2-WTI 36 μg/animal ip(IL-2-WTI bid x 5 then 2-day pause then bid x 5 then 2-day pause) #−Control Group

Procedures:

Mice were anaesthetized with isoflurane for implant of cells to reducethe ulcerations. This portion of the study began on the day of implant(Day 1). Group 1 consisted of 33 CR female C57BL/6 mice set up with5×10⁵ MC38 tumor cells in 0% Matrigel subcutaneously in the flank.Groups 2-6 consisted of 33 CR female C57BL/6 mice set up with 5×10⁵ MC38tumor cells in 0% Matrigel sc in the left flank. The tumors from theprevious MC38 experiment (Example 27b) were implanted in the right flankof each animal. Cell Injection Volume was 0.1 mL/mouse. Age of controlmice at initiation was14 to 17 weeks. These mice were age matched tomice from the previous MC38 experiment (Example 27b). No dosing ofactive agent occurred during rechallenge. Body Weights were takebiweekly until end, as were caliper measurements. Any adverse reactionsor death were reported immediately. Any individual animal with a singleobservation of >than 30% body weight loss or three consecutivemeasurements of >25% body weight loss was euthanized. Endpoint was tumorgrowth delay (TGD). Animals were monitored individually. The endpoint ofthe experiment was a tumor volume of 1000 mm³ or 45 days, whichevercomes first. Responders were followed longer when possible. When theendpoint is reached, the animals were euthanized. Results are shown inFIG. 33.

Example 27f Treatment with ACP10, ACP11 Agents and Treatment:

Formulation Gr. N Agent dose Route Schedule  1^(#) 12 Vehicle — ip biwkx 2 2 8 ACP11 175 μg/animal ip biwk x 2 3 8 ACP11 300 μg/animal ip biwkx 2 4 8 ACP10 5 μg/animal ip biwk x 2 5 8 ACP10 10 μg/animal ip biwk x 26 8 ACP10 43 μg/animal ip biwk x 2 7 8 ACP10 43 μg/animal ip qwk x 2 8 8ACP10 172 μg/animal ip biwk x 2 9 8 IL-I2- 5 μg/animal ip bid for 5 daysfirst day 1 dose then HM-WTI 2-day pause then bid for 5 days first day 1dose then 2-day pause 10  8 IL-12- 20 μg/animal ip bid for 5 days firstday 1 dose then HM-WTI 2-day pause then bid for 5 days first day 1 dosethen 2-day pause

Procedures:

Mice were anaesthetized with isoflurane for implant of cells to reducethe ulcerations. CR female C57BL/6 mice were set up with 5×10⁵ MC38tumor cells in 0% Matrigel sc in flank. Cell Injection Volume was 0.1mL/mouse. Mouse age at start date was 8 to 12 weeks. Pair matches wereperformed when tumors reach an average size of 100-150 mm³ and begintreatment. ACP11 was dosed at 175 or 300 μg/animal; ACP10 was dosed at5, 10, 43, or 172 ug/animal; IL-12-HM-WTI was dosed at 5 or 20ug/animal. Body weights were taken at initiation and then biweekly tothe end. Caliper measurements were taken biweekly to the end. Anyadverse reactions were to be reported immediately. Any individual animalwith a single observation of >than 30% body weight loss or threeconsecutive measurements of >25% body weight loss was euthanized. Anygroup with a mean body weight loss of >20% or >10% mortality stoppeddosing; the group was not euthanized and recovery is allowed. Within agroup with >20% weight loss, individuals hitting the individual bodyweight loss endpoint were euthanized. If the group treatment relatedbody weight loss is recovered to within 10% of the original weights,dosing resumed at a lower dose or less frequent dosing schedule.Exceptions to non-treatment body weight % recovery were allowed on acase-by-case basis. Endpoint was tumor growth delay (TGD). Animals weremonitored individually. The endpoint of the experiment was a tumorvolume of 1500 mm³ or 45 days, whichever comes first. Responders werefollowed longer. When the endpoint was reached, the animals are to beeuthanized. Results are shown in FIG. 45 and FIGS. 46A-46D.

Example 27g Treatment with ACP16, APC153, ACP155, ACP156 and ACP292

Agents and Treatment: Formulation Gr. N Agent dose Route Schedule  1^(#)12 Vehicle — ip biwk x 2 2 8 ACP16 17 μg/animal ip biwk x 2 3 8 ACP16 55μg/animal ip biwk x 2 4 8 ACP16 230 μg/animal ip biwk x 2 5 8 ACP155 55μg/animal ip biwk x 2 6 8 ACP155 230 μg/animal ip biwk x 2 7 8 ACP153 55μg/animal ip biwk x 2 8 8 ACP153 230 μg/animal ip biwk x 2 9 8 ACP156 55μg/animal ip biwk x 2 10  8 ACP156 230 μg/animal ip biwk x 2 11  8ACP292 45 μg/animal ip biwk x 2 12  8 ACP292 186 μg/animal ip biwk x 2

Procedures:

Mice were anaesthetized with isoflurane for implant of cells to reducethe ulcerations. CR female C57BL/6 mice were set up with 5×10⁵ MC38tumor cells in 0% Matrigel sc in flank. Cell Injection Volume was 0.1mL/mouse. Mouse age at start date was 8 to 12 weeks. Pair matches wereperformed when tumors reach an average size of 100-150 mm³ and begintreatment. ACP16 was dosed at 17, 55 or 230 μg/animal; ACP153, ACP155and ACP156 were dosed at 55 or 230 μg/animal; ACP292 was dosed at 45 or186 μg/animal. Body weights were taken at initiation and then biweeklyto the end. Caliper measurements were taken biweekly to the end. Anyadverse reactions were to be reported immediately. Any individual animalwith a single observation of >than 30% body weight loss or threeconsecutive measurements of >25% body weight loss was euthanized. Anygroup with a mean body weight loss of >20% or >10% mortality stoppeddosing; the group was not euthanized and recovery is allowed. Within agroup with >20% weight loss, individuals hitting the individual bodyweight loss endpoint were euthanized. If the group treatment relatedbody weight loss is recovered to within 10% of the original weights,dosing resumed at a lower dose or less frequent dosing schedule.Exceptions to non-treatment body weight % recovery were allowed on acase-by-case basis. Endpoint was tumor growth delay (TGD). Animals weremonitored individually. The endpoint of the experiment was a tumorvolume of 1500 mm³ or 45 days, whichever comes first. Responders werefollowed longer. When the endpoint was reached, the animals are to beeuthanized. Results are shown in FIGS. 49A-491.

Example 27h Treatment with ACP16, APC302 and ACP314

Agents and Treatment: Formulation Gr. N Agent dose Route Schedule  1^(#)12 Vehicle — ip biwk x 2 2 9 ACP16 55 μg/animal ip biwk x 2 3 9 ACP16230 μg/animal ip biwk x 2 4 9 ACP302 33 μg/animal ip biwk x 2 5 9 ACP302106 μg/animal ip biwk x 2 6 9 ACP302 442 μg/animal ip biwk x 2 7 9ACP302 1,344 μg/animal ip biwk x 2 8 9 ACP314 21 μg/animal ip biwk x 2 99 ACP314 68 μg/animal ip biwk x 2 10  9 ACP314 283 μg/animal ip biwk x 211  9 ACP314 861 μg/animal ip biwk x 2

Procedures:

Mice were anaesthetized with isoflurane for implant of cells to reducethe ulcerations. CR female C57BL/6 mice were set up with 5×10⁵ MC38tumor cells in 0% Matrigel sc in flank. Cell Injection Volume was 0.1mL/mouse. Mouse age at start date was 8 to 12 weeks. Pair matches wereperformed when tumors reach an average size of 100-150 mm³ and begintreatment. ACP16 was dosed at 55 or 230 μg/animal; ACP302 was dosed at33, 106, 442 or 1344 ug/animal; ACP314 was dosed at 21,68, 283 or 861μg/animal. Body weights were taken at initiation and then biweekly tothe end. Caliper measurements were taken biweekly to the end. Anyadverse reactions were to be reported immediately. Any individual animalwith a single observation of >than 30% body weight loss or threeconsecutive measurements of >25% body weight loss was euthanized. Anygroup with a mean body weight loss of >20% or >10% mortality stoppeddosing; the group was not euthanized and recovery is allowed. Within agroup with >20% weight loss, individuals hitting the individual bodyweight loss endpoint were euthanized. If the group treatment relatedbody weight loss is recovered to within 10% of the original weights,dosing resumed at a lower dose or less frequent dosing schedule.Exceptions to non-treatment body weight % recovery were allowed on acase-by-case basis. Endpoint was tumor growth delay (TGD). Animals weremonitored individually. The endpoint of the experiment was a tumorvolume of 1500 mm³ or 45 days, whichever comes first. Responders werefollowed longer. When the endpoint was reached, the animals are to beeuthanized. Results are shown in FIG. 50A and FIG. 50B.

Example 27i Treatment with ACP339

Agents and Treatment: Gr. N Agent Formulation dose Route Schedule  1^(#)12 Vehicle — ip biwk x 2 2 9 ACP339 55 μg/animal ip biwk x 2 3 9 ACP339230 μg/animal ip biwk x 2 4 9 ACP339 700 μg/animal ip biwk x 2

Procedures:

Mice were anaesthetized with isoflurane for implant of cells to reducethe ulcerations. CR female C57BL/6 mice were set up with 5×10⁵ MC38tumor cells in 0% Matrigel sc in flank. Cell Injection Volume was 0.1mL/mouse. Mouse age at start date was 8 to 12 weeks. Pair matches wereperformed when tumors reach an average size of 100-150 mm³ and begintreatment. ACP339 was dosed at 55, 230 or 700 μg/animal. Body weightswere taken at initiation and then biweekly to the end. Calipermeasurements were taken biweekly to the end. Any adverse reactions wereto be reported immediately. Any individual animal with a singleobservation of >than 30% body weight loss or three consecutivemeasurements of >25% body weight loss was euthanized. Any group with amean body weight loss of >20% or >10% mortality stopped dosing; thegroup was not euthanized and recovery is allowed. Within a groupwith >20% weight loss, individuals hitting the individual body weightloss endpoint were euthanized. If the group treatment related bodyweight loss is recovered to within 10% of the original weights, dosingresumed at a lower dose or less frequent dosing schedule. Exceptions tonon-treatment body weight % recovery were allowed on a case-by-casebasis. Endpoint was tumor growth delay (TGD). Animals were monitoredindividually. The endpoint of the experiment was a tumor volume of 1500mm³ or 45 days, whichever comes first. Responders were followed longer.When the endpoint was reached, the animals are to be euthanized. Resultsare shown in FIGS. 51A-51C.

Example 28

CT26 Experiments

The CT26 cell line, a rapidly growing colon adenocarcinoma cell linethat expresses MMP9 in vitro, was used. Using this tumor model, theability of fusion proteins to affect tumor growth was examined.

Example 28a

Treatment with ACP16 Alone or in Combination with Anti-PD1 Antibody

Agents and Treatment:

Formulation Gr. N Agent dose Route Schedule  1^(#) 12 vehicle 1// na//ip//ip days 1, 4, 8, 11// vehicle 2 na days 3, 6, 10, 13 2 10 vehicle1// na// ip//ip days 1, 4, 8, 11// ACP16 70 μg/animal days 3, 6, 10, 133 10 vehicle 1// na// ip//ip days 1, 4, 8, 11// ACP16 232 μg/animal days3, 6, 10, 13 4 10 vehicle 1// na// ip//ip days 1, 4, 8, 11// ACP16 500μg/animal days 3, 6, 10, 13 5 10 anti-PD-1 RMP1-14// 200 μg/animal//ip//ip days 1, 4, 8, 11// vehicle 2 na days 3, 6, 10, 13 6 10 anti-PD-1RMP1-14// 200 μg/animal// ip//ip days 1, 4, 8, 11// ACP16 70 μg/animaldays 3, 6, 10, 13 7 10 anti-PD-1 RMP1-14// 200 μg/animal// ip//ip days1, 4, 8, 11// ACP16 232 μg/animal days 3, 6, 10, 13 8 10 anti-PD-1RMP1-14// 200 μg/animal// ip//ip days 1, 4, 8, 11// ACP 16 500 μg/animaldays 3, 6, 10, 13 9 10 vehicle 1// na// ip//ip days 1, 4, 8, 11// IL-212 μg/animal bid x 5 first day 1 dose per week x 2 10  10 anti-PD-1RMP1-14// 200 μg/animal// ip//ip days 1, 4, 8, 11// IL-2 12 μg/animalbid x 5 first day 1 dose per week x 2

Procedures:

Mice were anaesthetized with isoflurane for implant of cells to reducethe ulcerations. CR female BALB/c mice were set up with 3×10⁵ CT26 tumorcells in 0% Matrigel sc in flank. Cell Injection Volume was 0.1mL/mouse. Mouse age at start date was 8 to 12 weeks. Pair matches wereperformed when tumors reach an average size of 100-150 mm³ and begintreatment. ACP16 was dosed at 70, 230 or 500 μg/animal with or withoutanti-PD-1 antibody (RMP1-14) at 200 μg/animal. Body weights were takenat initiation and then biweekly to the end. Caliper measurements weretaken biweekly to the end. Any adverse reactions were to be reportedimmediately. Any individual animal with a single observation of >than30% body weight loss or three consecutive measurements of >25% bodyweight loss was euthanized. Any group with a mean body weight lossof >20% or >10% mortality stopped dosing; the group was not euthanizedand recovery is allowed. Within a group with >20% weight loss,individuals hitting the individual body weight loss endpoint wereeuthanized. If the group treatment related body weight loss is recoveredto within 10% of the original weights, dosing resumed at a lower dose orless frequent dosing schedule. Exceptions to non-treatment body weight %recovery were allowed on a case-by-case basis. Endpoint was tumor growthdelay (TGD). Animals were monitored individually. The endpoint of theexperiment was a tumor volume of 1500 mm³ or 45 days, whichever comesfirst. Responders were followed longer. When the endpoint was reached,the animals are to be euthanized. Results are shown in FIGS. 47A-47D andFIGS. 48A-48B.

Example 29 Human Tblast Assay

Pre-stimulated T cells (T-blasts) were used to assess the activity ofinducible IL-2 fusion proteins. T-Blasts were induced from human PBMCswith a 3-day incubation with PHA. Tblasts were then plated in suspensionat a concentration of 50,000 or 75,000 cells/well in X-VIVO culturemedia (containing human serum albumin) and stimulated with a dilutionseries of recombinant IL-2 fusion proteins or human IL-2 for 72 hours at37° C. and 5% CO₂. Activity of uncleaved and cleaved IL-2 fusionproteins was tested. Cleaved inducible IL-2 was generated by incubationwith active MMP9. IL-2 activity was assessed measuring proliferationwith CellTiter-Glo.

Sample fusion protein constructs are detailed in Table 3. In table 3,“L” is an abbreviation of “linker”, and “cleay. link.” is anabbreviation of “cleavable linker”. Other abbreviations “mIFNg”indicates mouse interferon gamma (IFNg); “hAlbumin” indicates humanserum albumin (HSA); “mAlbumin” indicates mouse serum albumin.

TABLE 3 CONSTRUCT PERMUTATION TABLE (“6xHis” disclosed as SEQ ID NO:354) Construct Name Construct Description ACP01 (anti-HSA)-(cleav.link.)-mouse IFNg-(cleav. link.)-(anti-HSA)-6xHis ACP02(anti-HSA)-(cleav. link.)-mouse IFNg-(cleav. link.)-mouse IFNg-(cleav.link.)-(anti- HSA)-6xHis ACP03 (anti-HSA)-(cleav. link.)-mouseIFNg-mouse IFNg-(cleav. link.)-(anti-HSA)-6xHis ACP50(anti-EpCAM)-(anti-HSA)-(cleav. link.)-mouse IFNg-mouse IFNg-(cleav.link.)-(anti- HSA)-6xHis ACP51 (anti-EpCAM)-Linker-(anti-HSA)-(cleav.link.)-mIFNg-(cleav. link.)-(anti-HSA)- 6xHis ACP52 (anti-HSA)-(cleav.link.)-mIFNg-(cleav. link.)-(anti-HSA)-Linker-(anti-EpCAM)- 6xHis ACP53mAlbumin-(cleav. link.)-mIFNg-(cleav. link.)-mAlbumin-6xHis ACP54mAlbumin-(cleav. link.)-mIFNg-Linker-mIFNg-(cleav. link.)-mAlbumin-6xHisACP30 (anti-HSA)-(cleav. link.)-mouse IFNg-(cleav.link.)-(anti-HSA)-(cleav. link.)-mouse IFNg-(cleav.link.)-(anti-HSA)-6xHis ACP55 (anti-HSA)-(cleav. link.)-mouseIFNg-(cleav. link.)-(anti-HSA)-(cleav. link.)-mouse IFNg-(cleav.link.)-(anti-HSA)-6xHis-C-tag ACP56(anti-FOLR1)-Linker-(anti-HSA)-(cleav. link.)-mIFNg-(cleav.link.)-(anti-HSA)-6xHis ACP57 (anti-HSA)-(cleav. link.)-mIFNg-(cleav.link.)-(anti-HSA)-Linker-(anti-FOLR1)-6xHis ACP58 (anti-HSA)-(cleav.link.)-mIFNg-(cleav. link.)-mIFNg-(cleav. link.)-(anti-HSA)-Linker-(anti-EpCAM)-6xHis ACP59 (anti-FOLR1)-Linker-(anti-HSA)-(cleav.link.)-mIFNg-(cleav. link.)-mIFNg-(cleav. link.)-(anti-HSA)-6xHis ACP60(anti-HSA)-(cleav. link.)-mIFNg-(cleav. link.)-mIFNg-(cleav.link.)-(anti-HSA)- Linker-(anti-FOLR1)-6xHis ACP61 (anti-HSA)-(cleav.link.)-mIFNg-(cleav. link.)-mIFNg-(cleav. link.)-(anti-HSA)-Linker-FN(CGS-2)-6xHis ACP63 anti-FN CGS-2 scFv (Vh/Vl)-6xHis ACP69(anti-HSA)-(cleav. link.)-mouse IFNg-(cleav. link.)-(anti-HSA)-(cleav.link.)-mouse IFNg ACP70 mouse IFNg-(cleav. link.)-(anti-HSA)-(cleav.link.)-mouse IFNg-(cleav. link.)-(anti- HSA) ACP71 mouse IFNg-(cleav.link.)-mAlbumin-(cleav. link.)-mouse IFNg-(cleav. link.)- mAlbumin ACP72mAlbumin-(cleav. link.)-mouse IFNg-(cleav. link.)-mAlbumin-(cleav.link.)-mouse IFNg ACP73 mAlbumin-(cleav. link.)-mouse IFNg-(cleav.link.)-mAlbumin-(cleav. link.)-mouse IFNg-(cleav. link.)-mAlbumin ACP74mAlbumin-(cleav. link.)-mouse IFNg-(cleav. link.)-5merlinker-mAlbumin-5mer linker-(cleav. link.)-mouse IFNg-(cleav.link.)-mAlbumin ACP75 mAlbumin-(cleav. link.)-mouse IFNg-(cleav.link.)-10mer linker-mAlbumin-10mer linker-(cleav. link.)-mouseIFNg-(cleav. link.)-mAlbumin ACP78(anti-HSA)-Linker-mouse_IFNg-Linker-(anti-HSA)-Linker-mouse_IFNg-Linker-(anti-HSA)_(non-cleavable_control) ACP134 Anti-HSA-(cleav.link.)-mouse_IFNg-(cleav. link.)-anti-HSA-(cleav. link.)-mouse_IFNg-(cleav. link.)-anti-HSA-L-anti-FOLR1 ACP 135Anti-FOLR1-L-HSA-(cleav. link.)-mouse_IFNg-(cleav. link.)-HSA-(cleav.link.)- mouse_IFNg-(cleav. link.)-HSA ACP04 human p40-murine p35-6xHisACP05 human p40-human p35-6xHis ACP34 mouse p35-(cleav. link.)-mousep40-6xHis ACP35 mouse p35-GS-(cleav. link.)-GS-mouse p40-6xHis ACP36(anti-HSA)-(Cleav. Linker)-mouse p40-mouse p35-(Cleav.Linker)-(anti-HSA)-6xHis ACP37 (anti-EpCAM)-(anti-HSA)-(Cleav.Linker)-mouse p40-mouse p35-(Cleav. Linker)- (anti-HSA)-6xHis ACP79(anti-EpCAM)-Linker-(anti-HSA)-(cleav. link.)-mIL12-(cleav.link.)-(Anti-HSA)- 6xHis ACP80 (anti-HSA)-(cleav. link.)-mIL12-(cleav.link.)-(anti-HSA)-Linker-(anti-EpCAM)- 6xHis ACP06Blocker12-Linker-(cleav. link.)-human p40-Linker-mouse p35-(cleav.link.)-(anti- HSA)-6xHis ACP07 Blocker12-Linker-(cleav. link.)-humanp40-Linker-mouse p35-(cleav. link.)-(anti-HSA)-Linker-(anti-FOLR1)-6xHis ACP08(anti-FOLR1)-Linker-Blocker12-Linker-(cleav. link.)-humanp40-Linker-mouse p35- (cleav. link.)-(anti-HSA)-6xHis ACP09(anti-HSA)-Linker-Blocker12-Linker-(cleav. link.)-human p40-Linker-mousep35- 6xHis ACP10 (anti-HSA)-(cleav. link.)-human p40-L-mouse p35-(cleav.link.)-Linker-Blocker12-6xHis ACP11 Human_p40-Linker-mouse_p35-(cleav.link.)-Linker-Blocker12-Linker-(anti-HSA)-6xHis ACP91human_p40-Linker-mouse_p35-Linker-Linker-Blocker-Linker-(anti-HSA)_(non-cleavable control) ACP136 human p40-L-mouse p35-(cleav. link.)-BlockerACP138 human_p40-L-mouse_p35-(cleav. link.)-Blocker-L-(anti-HSA)-L-FOLR1ACP139 Anti-FOLR1-L-human_p40-L-mouse_p35-(cleav.link.)-Blocker12-L-(anti-HSA) ACP140 Anti-FOLR1-(cleav.link.)-human_p40-L-mouse_p35-(cleav. link.)-Blocker12-L-(anti-HSA) ACP12(anti-EpCAM)-IL2-(cleav. link.)-(anti-HSA)-blocker2-6xHis ACP13(anti-EpCAM)-Blocker2-(anti-HSA)-(cleav. link.)-IL2-6xHis ACP14Blocker2-Linker-(cleav. link.)-IL2- (cleav. link.)-(anti-HSA)-6xHisACP15 Blocker2-Linker-(anti-HSA)-Linker-(cleav. link.)- IL2 -6xHis ACP16IL2-(cleav. link.)-(anti-HSA)-Linker-(cleav. link.)-Blocker2-6xHis ACP17(anti-EpCAM)-Linker-IL2-(cleav. link.)-(anti-HSA)-Linker-(cleav.link.)-Blocker2-6xHis ACP18 (anti-EpCAM)-Linker-IL2-(clcav.link.)-(anti-HSA)-Linker-vh(cleav. link.)vl-6xHis ACP19 IL2-(cleav.link.)-Linker-Blocker2-Linker-(anti-HSA)-Linker-(anti-EpCAM) -6xHisACP20 IL2-(cleav. link.)-Blocker2-6xHis ACP21 IL2-(cleav.link.)-Linker-Blocker2-6xHis ACP22 IL2-(cleav.link.)-Linker-blocker-(cleav.link.)-(anti-HSA)-Linker-(anti-EpCAM)-6xHis ACP23 (anti-FOLR1)-(cleav.link.)-Blocker2-Linker-(cleav. link.)-(anti-HSA)-(cleav.link.)-IL2-6xHis ACP24 (Blocker2)-(cleav. link.)-(IL2)-6xHis ACP25Blocker2-Linker-(cleav. link.)-IL2-6xHis ACP26(anti-EpCAM)-Linker-IL2-(cleav. link.)-(anti-HSA)-Linker-blocker(NARA1Vh/Vl) ACP27 (anti-EpCAM)-Linker-IL2-(cleav.link.)-(anti-HSA)-Linker-blocker(NARA1 Vl/Vh) ACP28 IL2-(cleav.link.)-Linker-Blocker2-(NARA1Vh/Vl)-Linker-(anti-HSA)-Linker-(anti-EpCAM) ACP29 IL2-(cleav.link.)-Linker-Blocker2-(NARA1Vl/Vh)-Linker-(anti-HSA)-Linker-(anti-EpCAM) ACP38 IL2-(cleav.link.)-blocker-(anti-HSA)-(anti-EpCAM)-6xHis ACP39 (anti-EpCAM)-(cleav.link.)-(anti-HSA)-(cleav. link.)-Blocker2-(cleav. link.)-IL-2-6xHisACP40 CD25ecd-Linker-(cleav. link.)-IL2-6xHis ACP41 IL2-(cleav.link.)-Linker-CD25ecd-6xHis ACP42(anti-HSA)-Linker-CD25ecd-Linker-(cleav. link.)-IL2-6xHis ACP43IL2-(cleav. link.)-Linker-CD25ecd-Linker-(anti-HSA)-6xHis ACP44IL2-(cleav. link.)-Linker-CD25ecd-(cleav. link.)-(anti-HSA)-6xHis ACP45(anti-HSA)-(cleav. link.)-Blocker2-Linker-(cleav. link.)-IL2-6xHis ACP46IL2-(cleav. link.)-linkerL-vh(cleav.link.)vl-Linker-(anti-HSA)-L-(anti-EpCAM)-6xHis ACP47(anti-EpCAM)-Linker-IL2-(CleavableLinker)-(anti-HSA)-Linker-Blocker2-6xHis ACP48 IL2-(cleav.link.)-Blocker2-Linker-(anti-HSA)-6xHis ACP49 IL2-(cleav.link.)-Linker-Blocker2-Linker-(anti-HSA)-6xHis ACP92 (anti-HSA)-(16merCleav. Link.)-IL2-(16mer Cleav. Link.)-(anti-HSA)-6XHis ACP93(anti-EpCAM)-(anti-HSA)-(anti-EpCAM)-Blocker2-(cleav. link.)-IL2-6xHisACP94 (anti-EpCAM)-(anti-HSA)-Blocker2-(cleav. link.)-IL2-6xHis ACP95(anti-EpCAM)-(anti-HSA)-(cleav. link.)-IL2-6xHis ACP96(anti-EpCAM)-(16mer cleav. link.)-IL2-(16mer cleav. link.)-(anti-HSA)ACP97 (anti-EpCAM)-(anti-HSA)-(cleav. link.)-IL2-(cleav.link.)-(anti-HSA)-6xHis ACP99 (anti-EpCAM)-Linker-IL2-(cleav.link.)-(anti-HSA)-6xHis ACP100 (anti-EpCAM)-Linker-IL2-6xHis ACP101IL2-(cleav. link.)-(anti-HSA)-6xHis ACP102 (anti-EpCAM)-(cleav.link.)-IL2-(cleav. link.)-(anti-HSA)-Linker-blocker-6xHis ACP103IL2-(cleav.link.)-Linker-Blocker2-Linker-(anti-HSA)-Linker-(antiI-FOLR1)-6xHisACP104 (anti-FOLR1)-IL2-(cleav. link.)-(anti-HSA)-Linker-Blocker2-6xHisACP105 Blocker2-Linker-(cleav. link.)-IL2-(cleav.link.)-(anti-HSA)-Linker-(anti-FOLR1)-6xHis ACP106(anti-FOLR1)-Linker-(anti-HSA)-(cleav. link.)-blocker-Linker-(cleav.link.)-IL2 -6xHis ACP107 Blocker2-Linker-(anti-HSA)-(cleav.link.)-IL2-Linker-(anti-FOLR1)-6xHis ACP108 (anti-EpCAM)-IL2-(Duallycleav. link.)-(anti-HSA)-Linker-blocker-6xHis ACP117 anti-FN CGS-2 scFv(Vh/Vl)-6xHis ACP118 NARA1 Vh/Vl non-cleavable ACP119 NARA1 Vh/Vlcleavable ACP120 NARA1 Vl/Vh non-cleavable ACP121 NARA1 Vl/Vh cleavableACP124IL2-Linker-(anti-HSA)-Linker-Linker-blocker_(non-cleavable_control)ACP132 IL2-L-HSA ACP141 IL2-L-human_Albumin ACP142 IL2-(cleav.link.)-human_Albumin ACP144 IL2-(cleav.link.)-HSA-(cleav.-link.)blocker-L-(anti-FOLR1) ACP145Anti-FOLR1-L-IL2-(cleav. link.)-HSA-Linker-(cleav. link.)-blocker2ACP146 Anti-FOLR1-(cleav. link)-IL2-(cleav. link.)-HSA-Linker-(cleav.link.)-blocker2 ACP133 IL2-6x His ACP147 IL2-(cleav.Linker)-(anti-HSA)-Linker-(cleav. link.)-blocker2-L-(anti-EpCAM) ACP148(anti-EpCAM)-L-IL2-(cleav. link.)-(anti-HSA)-L-(cleav. Linker)-blocker2ACP149 (anti-EpCAM)-(cleav. link.)-IL2-(cleav.Linker)-(anti-HSA)-L-(cleav. Linker)-blocker2 ACP31 (anti-HSA)-(cleav.link.)-mIFNa1-(cleav. link.)-(anti-HSA) ACP32 (anti-HSA)-(cleav.link.)-mIFNa1(N + C trunc)-(cleav. link.)-(anti-HSA) ACP33(anti-HSA)-(cleav. link.)-mIFNa1(C trunc)-(cleav. link.)-(anti-HSA)ACP131 mIFNa1 ACP125 Anti-HSA-(cleav. link.)-mIFNa1 ACP126mIFNa1-(cleav. link.)-(anti-HSA) ACP127 Mouse_Albumin-(cleav.Link.)-mIFNa1-(cleav link)-mouse_Albumin ACP128 Mouse_Albumin-(cleav.link.)-mIFNa1 ACP129 mIFNa1-(cleav. link.)-mAlb ACP150(Anti-FOLR1)-L-(anti-HSA)-(cleav. Link.)-mIFNa1-(cleav.Link.)-(anti-HSA) ACP151 Anti-FOLR1-L-(anti-HSA)-(cleav.Link.)-mIFNa1-(cleav. Link.)-(anti-HSA)-L-(anti-FLOR1) ACP152(anti-HSA)-L-mIFNa1-L-(anti-HSA)_(non-cleavable_control) ACP153IL2-(cleav. link.)-(anti-HSA)-linker(cleav. link.)-blocker2 ACP154IL2-(cleav. link.)-(anti-HSA)-linker(cleav. link.)-blocker2 ACP155IL2-(cleav. link.)-(anti-HSA)-linker(cleav. link.)-blocker2 ACP156IL2-(cleav. link.)-(anti-HSA)-linker(cleav. link.)-blocker2 ACP157IL2-(cleav. link.)-(anti-HSA)-linker(cleav. link.)-blocker2 ACP200mAlb(D3)-X-mouse-IFNa-X-mAlb(D3)_(X = MMP9-M) ACP201mAlb(D1-L-D3)-X-mouse-IFNa-X-mAlb(D1-L-D3)_(X = MMP9-M) ACP202HSA-X-mIFNa1-X-HSA_(X = MMP9-M + 17aa) ACP203 HSA-X-mIFNa1-X-HSA_(X =MMP14-1) ACP204 HSA-X-mIFNa1-X-HSA_(X = CTSL1-1) ACP205HSA-X-mIFNa1-X-HSA_(X = ADAM17-2) ACP206 HSA-X-Human_IFNA2b-X-HSA_(X =MMP14-1) ACP207 HSA-X-Human_IFNA2b-X-HSA_(X = CTSL1-1) ACP208HSA-X-Human_IFNA2b-X-HSA_(X = ADAM17-2) ACP211HSA-X-mouse-IFNg-X-IFNa-X-mouse-IFNg-X-HSA_(X = MMP9-M) ACP213mAlb(D3)-X-mouse-IFNg-X-mAlb(D3)-X-mouse-IFNg-X-mAlb(D3)_(X = MMP9-M)ACP214mAlb(D1-L-D3)-X-mouse-IFNg-X-mAlb(D1-L-D3)-X-mouse-IFNg-X-mAlb(D1-L-D3)_(X= MMP9-M) ACP215 HSA-X-mouse-IFNg-X-HSA-X-mouse-IFNg-X-HSA_(X = MMP9-M +17aa) ACP240 HSA-L-human_p40-L-mouse_p35-LL-Blocker_(non-cleavable;Blocker = briakinumab_Vl/Vh) ACP241mAlb-X-human_p40-L-mouse_p35-XL-Blocker_(X = MMP9-M; Blocker =briakinumab_Vl/Vh) ACP242 human_p40-L-mouse_p35-XL-Blocker-X-mAlb_(X =MMP9-M; Blocker = briakinumab_Vl/Vh) ACP243mIgG1_Fc-X-human_p40-L-mouse_p35-XL-Blocker_(X = MMP9-M; Blocker =briakinumab_Vl/Vh) ACP244 human_p40-L-mouse_p35-XL-Blocker-X-mIgGl_Fc_(X= MMP9-M; Blocker = briakinumab_Vl/Vh) ACP245HSA-X-human_p40-L-mouse_p35-XL-Blocker(cleavable)_(X = MMP9-M; Blocker =briakinumab_Vl-X-Vh) ACP247HSA-X-human_p40-L-mouse_p35-XL-Blocker_(Blocker = 3CYT5; X = MMP9-M)ACP284 HSA-X-mouse_p35-XL-Blocker_(Blocker = briakinumab_Vl/Vh; X =MMP9-M) ACP285 HSA-X-human_p40_C199S-L-mouse_p35C92S-XL-Blocker_(Blocker = briakinumab_Vl/Vh; X = MMP9-M) ACP286HSA-X-human p40-L(4xG4S (SEQ ID NO: 453))-mouse p35-XL-Blocker_(Blocker= briakinumab_Vl/Vh; X = MMP9-M) ACP287HSA-X-human_p40_mouse_p35-XL-Blocker_(Blocker =briakinumab_Vl/Vh_VH44-VL100_disulfide; X = MMP9-M) ACP288HSA-X-human_p40_mouse_p35-XL-Blocker_(Blocker =briakinumab_Vl/Vh_VH105-VL43_disulfide; X = MMP9-M) ACP289Geneart_WW0048_IL2-X-HSA-LX-blocker_Fusion_protein-6xHis ACP290IL2-X-HSA-LX-blocker_(X = MMP9-M; Blocker = 3TOW69) ACP291IL2-X-HSA-LX-blocker_(X = MMP9-M; Blocker = 3TOW85) ACP292IL2-X-HSA-LX-blocker_(X = MMP9-M; Blocker = 2TOW91) ACP296IL2-X-HSA-LX-blocker(cleavable)_(X = MMP9-M; Blocker = MT204_Vh-X-Vl)ACP297 IL2-X-HSA-LX-blocker(A46L)_(X = MMP9-M; Blocker = MT204_Vh/Vl)ACP298 IL2-X-HSA-LX-blocker(A46G)_(X = MMP9-M; Blocker = MT204_Vh/Vl)ACP299 IL2(Cysl45Ser)-X-HSA-LX-blocker_(X = MMP9-M; Blocker =MT204_Vh/Vl) ACP300 IL2-X-hAlb-LX-blocker_(X = MMP9-M; Blocker =MT204_Vh/Vl) ACP302 IL2-X-mAlb-LX-blocker_(X = MMP9-M; Blocker =MT204_Vh/Vl) ACP303 mAlb-X-IL2(Nterm-41)-X-mALB_(X = MMP9-M) ACP304IL2-X-HSA-LX-blocker-XL-CD25ecd_(X = MMP9-M; Blocker = MT204_Vh/Vl)ACP305 CD25ecd-LX-IL2-X-HSA-LX-blocker_(X = MMP9-M; Blocker =MT204_Vh/Vl) ACP306 IL2-XL-CD25ecd-X-HSA-LX-blocker_(X = MMP9-M; Blocker= MT204_Vh/Vl) ACP309 IL2-X-HSA-LX-blocker(A46S)_(X = MMP9-M; Blocker =MT204_Vh/Vl) ACP310 IL2-X-HSA-LX-blocker(QAPRL_FR2)_(X = MMP9-M; Blocker= MT204_Vh/Vl) ACP311 IL2-X-IgG4_Fc(S228P)-LX-Blocker_(X = MMP9-M;Blocker = MT204_Vh/Vl) ACP312 IgG4_Fc(S228P)-X-IL2-LX-Blocker_(X =MMP9-M; Blocker = MT204_Vh/Vl) ACP313 IL2-XL-Blocker-X-IgG4_Fc(S228P)_(X= MMP9-M; Blocker = MT204_Vh/Vl) ACP314 mIgG1_Fc-X-IL2-LX-Blocker_(X =MMP9-M; Blocker = MT204_Vh/Vl) ACP336 IL2-X-anti-HSA-LX-blocker_(Blocker= VHVL.F2.high.A02_Vh-X-Vl_A46S; X = MMP14-1) ACP337IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_A46S; X =MMP14-1) ACP338 IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.F03_Vh-X-Vl; X = MMP14-1) ACP339IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.F03_Vh/Vl; X =MMP14-1) ACP340 IL2-X-anti-HSA-LX-blocker_(Blocker = Hu2TOW91_B; X =MMP14-1) ACP341 IL2-X-anti-HSA-LX-blocker_(Blocker = Hu3TOW85_A; X =MMP14-1) ACP342 CD25ecd_C213S-LX-IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh-X-Vl_A46S; X = MMP14-1) ACP343CD25ecd_C213S-LX-IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh/Vl_A46S; X = MMP14-1) ACP344CD25ecd_C213S-LX-IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.F03_Vh-X-Vl; X = MMP14-1) ACP345CD25ecd_C213S-LX-IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.F03_Vh/Vl; X = MMP14-1) ACP346CD25ecd_C213S-LX-IL2-X-anti-HSA-LX-blocker_(Blocker = Hu2TOW91_B; X =MMP14-1) ACP347 CD25ecd_C213S-LX-IL2-X-anti-HSA-LX-blocker_(Blocker =Hu3TOW85_A; X = MMP14-1) ACP348 IgG4_Fc(S228P)-X-IL2-LX-Blocker_(Blocker= VHVL.F2.high.A02_Vh-X-Vl_A46S; X = MMP14-1) ACP349IgG4_Fc(S228P)-X-IL2-LX-Blocker_(Blocker = VHVL.F2.high.A02_Vh\Vl_A46S;X = MMP14-1) ACP350 IgG4_Fc(S228P)-X-IL2-LX-Blocker_(Blocker =VHVL.F2.high.F03_Vh-X-Vl; X = MMP14-1) ACP351IgG4_Fc(S228P)-X-IL2-LX-Blocker (Blocker = VHVL.F2.high.F03_Vh\Vl; X =MMP14-1) ACP352 IgG4_Fc(S228P)-X-IL2-LX-Blocker_(Blocker = Hu2TOW91_B; X= MMP14-1) ACP353 IgG4_Fc(S228P)-X-IL2-LX-Blocker_(Blocker = Hu3TOW85_A;X = MMP14-1) ACP354IgG4_Fc(S228P)-X-CD25ecd_C213S-LX-IL2-LX-Blocker_(Blocker =VHVL.F2.high.A02_Vh-X-Vl_A46S; X = MMP14-1) ACP355IgG4_Fc(S228P)-X-CD25ecd_C213S-LX-IL2-LX-Blocker_(Blocker =VHVL.F2.high.A02_Vh\Vl_A46S; X = MMP14-1) ACP356IgG4_Fc(S228P)-X-CD25ecd_C213S-LX-IL2-LX-Blocker_(Blocker =VHVL.F2.high.F03_Vh-X-V1; X = MMP14-1) ACP357IgG4_Fc(S228P)-X-CD25ecd_C213S-LX-IL2-LX-Blocker_(Blocker =VHVL.F2.high.F03_Vh\Vl; X = MMP14-1) ACP358IgG4_Fc(S228P)-X-CD25ecd_C213S-LX-IL2-LX-Blocker_(Blocker = Hu2TOW91_B;X = MMP14-1) ACP359IgG4_Fc(S228P)-X-CD25ecd_C213S-LX-IL2-LX-Blocker_(Blocker = Hu3TOW85_A;X = MMP14-1) ACP371 IL2-X-anti-HSA-LX-blocker_(Blocker =MT204_Vh/Vl_VH44-VL100_disulfide; X = MMP14-1) ACP372IL2-X-anti-HSA-LX-blocker_(Blocker = MT204_Vh/Vl_VH105-VL43_disulfide; X= MMP14-1) ACP373 IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh/Vl_VH44-VL100_disulfide; X = MMP14-1) ACP374IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh/Vl_VH105-VL43_disulfide; X = MMP14-1) ACP375IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.F03_Vh/Vl_VH44-VL100_disulfide; X = MMP14-1) ACP376IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.F03_Vh/Vl_VH105-VL43_disulfideX = MMP14-1) ACP377IL2-X-anti-HSA-LX-blocker_(Blocker = Hu2TOW91_A; X = MMP14-1) ACP378IL2-X-anti-HSA-LX-Heavy_blocker_Fab_(Blocker = MT204_VH-CH1; X =MMP14-1) ACP379 IgG4_Fc(S228P)-X-IL2-LX-Heavy_blocker_Fab_(Blocker =MT204_VH-CH1; X = MMP14-1) ACP383IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker =MT204_Vh/Vl_VH44-VL100_disulfide; X = MMP14-1) ACP384IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker =MT204_Vh/Vl_VH105-VL43_disulfide; X = MMP14-1) ACP385IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh/Vl_VH44-VL100_disulfide; X = MMP14-1) ACP386IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh/Vl_VH105-VL43_disulfide; X = MMP14-1) ACP387IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker =VHVL.F2.high.F03_Vh/Vl_VH44-VL100_disulfide; X = MMP14-1) ACP388IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker =VHVL.F2.high.F03_Vh/Vl_VH105-VL43_disulfide; X = MMP14-1) ACP389IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker = Hu2TOW91_A; X = MMP14-1)ACP390 IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh/Vl_A46S_VH44-VL100_disulfide; X = MMP14-1) ACP391IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh/Vl_A46S_VH44-VL100_disulfide; X = MMP14-1) ACP392IL2-XL-CD25ecd_C213S-X-HSA-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh_G44C_Vl_A46S_G100C; X = MMP14-1) ACP393IL2-XL-CD25ecd_C213S-X-HSA-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh_Q105C_Vl_A43C; X = MMP14-1) ACP394IL2-XL-CD25ecd_C213S-X-HSA-LX-blocker_(Blocker =VHVL.F2.high.F03_Vh_G44C_Vl_G100C; X = MMP14-1) ACP395IL2-XL-CD25ecd_C213S-X-HSA-LX-blocker_(Blocker =VHVL.F2.high.F03_Vh_Q105C_Vl_A43C; X = MMP14-1) ACP396IL2-XL-CD25ecd_C213S-X-HSA-LX-blocker_(Blocker = Hu2TOW91_A; X =MMP14-1) ACP397 IL2-XL-CD25ecd_C213S-X-HSA-LX-blocker_(Blocker =Hu2TOW91_B; X = MMP14-1) ACP398IL2-XL-CD25ecd_C213S-X-HSA-LX-Heavy_blocker_Fab_(Blocker = MT204_VH-CH1;X = MMP14-1) ACP399 Blocker-XL-HSA-X-IL2(Nterm-41)-X-HSA)_(Blocker =VHVL.F2.high.A02_Vh_G44C_Vl_A46S_G100C; X = MMP14-1) ACP400Blocker-XL-HSA-X-IL2(Nterm-41)-X-HSA_(Blocker =VHVL.F2.high.A02_Vh_Q105C_Vl_A43C; X = MMP14-1) ACP401Blocker-XL-HSA-X-IL2(Nterm-41)-X-HSA_(Blocker =VHVL.F2.high.F03_Vh_G44C_Vl_G100C; X = MMP14-1) ACP402Blocker-XL-HSA-X-IL2(Nterm-41)-X-HSA_(Blocker =VHVL.F2.high.F03_Vh_Q105C_Vl_A43C; X = MMP14-1) ACP403Blocker-XL-HSA-X-IL2(Nterm-41)-X-HSA_(Blocker = Hu2TOW91_A; X = MMP14-1)ACP404 Blocker-XL-HSA-X-IL2(Nterm-41)-X-HSA_(Blocker = Hu2TOW91_B; X =MMP14-1) ACP405 Heavy_Blocker_Fab-XL-HSA-X-IL2(Nterm-41)-X-HSA_(Blocker= MT204_VH-CH1; X = MMP14-1) ACP406mIgG1_Fc(S228P)-X-IL2-LX-Heavy_blocker_Fab_(Blocker = MT204_VH-CH1; X =MMP14-1) ACP407 mIgG1_Fc(S228P)-X-IL2-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh/Vl_VH44-VL100_disulfide; X = MMP14-1) ACP408mIgG1_Fc(S228P)-X-IL2-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh/Vl_A46S_VH44-VL100_disulfide; X = MMP14-1) ACP409mIgG1_Fc(S228P)-X-IL2-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh/Vl_VH105-VL43_disulfidel; X = MMP14-1) ACP410mIgG1_Fc(S228P)-X-IL2-LX-blocker_(Blocker =VHVL.F2.high.F03_Vh/Vl_VH44-VL100_disulfidel; X = MMP14-1) ACP411mIgG1_Fc(S228P)-X-IL2-LX-blocker_(Blocker =VHVL.F2.high.F03_Vh/Vl_VH105-VL43_disulfidel; X = MMP14-1) ACP412mIgG1_Fc(S228P)-X-IL2-LX-blocker_(Blocker = Hu2TOW91_A; X = MMP14-1)ACP413 CD25_213S-L-Kappa_blocker_Fab_(Blocker =VHVL.F2.high.A02_A46S_Kappa) ACP414CD25_213S-L-Kappa_blocker_Fab_(Blocker = VHVL.F2.high.F03_Kappa) ACP415IL2-XL-blocker-L-CD25_213S-X-HSA_Blocker =VHVL.F2.high.A02_Vh_G44C_Vl_A46S_G100C; X = MMP14-1) ACP416IL2-XL-blocker-L-CD25_213S-X-HSA_(Blocker =VHVL.F2.high.A02_Vh_Q105C_Vl_A43C; X = MMP14-1) ACP417IL2-XL-blocker-L-CD25_213S-X-HSA_(Blocker =VHVL.F2.high.F03_Vh_G44C_Vl_G100C; X = MMP14-1) ACP418IL2-XL-blocker-L-CD25_213S-X-HSA_(Blocker =VHVL.F2.high.F03_Vh_Q105C_Vl_A43C; X = MMP14-1) ACP419IL2-XL-blocker-L-CD25_213S-X-HSA_(Blocker = Hu2TOW91_A; X = MMP14-1)ACP420 IL2-XL-blocker-L-CD25_213S-X-HSA_(Blocker = Hu2TOW91_B; X =MMP14-1) ACP421 HSA-X-blocker-L-CD25_213S-LX-IL2_(Blocker =VHVL.F2.high.A02_Vh_G44C_Vl_A46S_G100C; X = MMP14-1) ACP422HSA-X-blocker-L-CD25_213S-LX-IL2_(Blocker =VHVL.F2.high.A02_Vh_Q105C_Vl_A43C; X = MMP14-1) ACP423HSA-X-blocker-L-CD25_213S-LX-IL2_(Blocker =VHVL.F2.high.F03_Vh_G44C_Vl_G100C; X = MMP14-1) ACP424HSA-X-blocker-L-CD25_213S-LX-IL2_(Blocker =VHVL.F2.high.F03_Vh_Q105C_Vl_A43C; X = MMP14-1) ACP425HSA-X-blocker-L-CD25_213S-LX-IL2_(Blocker = Hu2TOW91_A; X = MMP14-1)ACP426 HSA-X-blocker-L-CD25_213S-LX-IL2_(Blocker = Hu2TOW91_B; X =MMP14-1) ACP427 IL2-X-anti-HSA-LX-Blocker1-L-Blocker2_(Blocker1 =VHVL.F2.high.A02_Vh_G44C_Vl_A46S_G100C, Blocker2 = Hu2TOW91_A; X =MMP14-1) ACP428 IL2-X-anti-HSA-LX-Blocker1-L-Blocker2_(Blocker1 =VHVL.F2.high.A02_Vh_Q105C_Vl_A43C, Blocker2 = Hu2TOW91_A; X = MMP14-1)ACP429 IL2-X-anti-HSA-LX-Blocker1-L-Blocker2_(Blocker1 =VHVL.F2.high.F03_Vh_G44C_Vl_G100C, Blocker2 = Hu2TOW91_A; X = MMP14-1)ACP430 IL2-X-anti-HSA-LX-Blocker1-L-Blocker2_(Blocker1 =VHVL.F2.high.F03_Vh_Q105C_Vl_A43C, Blocker2 = Hu2TOW91_A; X = MMP14-1)ACP431 IL2-X-anti-HSA-LX-Blocker1-L-Blocker2_(Blocker1 =VHVL.F2.high.A02_Vh_G44C_Vl_A46S_G100C, Blocker2 = Hu2TOW91_B; X =MMP14-1) ACP432 IL2-X-anti-HSA-LX-Blocker1-L-Blocker2_(Blocker1 =VHVL.F2.high.A02_Vh_Q105C_Vl_A43C, Blocker2 = Hu2TOW91_B; X = MMP14-1)ACP433 IL2-X-anti-HSA-LX-Blocker1-L-Blocker2_(Blocker1 =VHVL.F2.high.F03_Vh_G44C_Vl_G100C, Blocker2 = Hu2TOW91_B; X = MMP14-1)ACP434 IL2-X-anti-HSA-LX-Blocker1-L-Blocker2_(Blocker1 =VHVL.F2.high.F03_Vh_Q105C_Vl_A43C, Blocker2 = Hu2TOW91_B; X = MMP14-1)ACP439 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.C07_Vh/Vl; X =MMP14-1) ACP440 IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.C07_Vh/Vl_A46S; X = MMP14-1) ACP441IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.C07_Vh/Vl_A46L; X =MMP14-1) ACP442 IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.C07_Vh/Vl_A46S_VH44-VL100_disulfide; X = MMP14-1) ACP443IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.C07_Vh/Vl_A46L_VH44-VL100_disulfide; X = MMP14-1) ACP444IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.C07_Vh/Vl_VH105-VL43_disulfide; X = MMP14-1) ACP445IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh-X-Vl_A46L; X =MMP14-1) ACP446 IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh/Vl_A46L; X = MMP14-1) ACP447IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh/Vl_A46L_VH44-VL100_disulfide; X = MMP14-1) ACP451IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_A46S; X =CTSL1-1) ACP452 IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.F03_Vh/Vl; X = CTSL1-1) ACP453IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh/Vl_A46S_VH44-VL100_disulfide; X = CTSL1-1) ACP454IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh/Vl_VH105-VL43_disulfidel; X = CTSL1-1) ACP455IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.F03_Vh/Vl_VH44-VL100_disulfide; X = CTSL1-1) ACP456IL2-X-anti-HSA-LX-blocker_(Blocker =VHVL.F2.high.F03_Vh/Vl_VH105-VL43_disulfideX = CTSL 1-1) ACP457IL2-X-anti-HSA-LX-Heavy_blocker_Fab_(Blocker = MT204_VH-CH1; X =CTSL1-1) ACP458 IgG4_Fc(S228P)-X-IL2-LX-Heavy_blocker_Fab_(Blocker =MT204_VH-CH1; X = CTSL1-1) ACP459IgG4_Fc(S228P)-X-IL2-LX-Blocker_(Blocker = VHVL.F2.high.A02_Vh\Vl_A46S;X = CTSL1-1) ACP460 IgG4_Fc(S228P)-X-IL2-LX-Blocker_(Blocker =VHVL.F2.high.F03_Vh\Vl; X = CTSL1-1) ACP461IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh/Vl_A46S_VH44-VL100_disulfide; X = CTSL1-1) ACP462IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh/Vl_VH105-VL43_disulfidel; X = CTSL1-1) ACP463IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker =VHVL.F2.high.F03_Vh/Vl_VH44-VL100_disulfidel; X = CTSL1-1) ACP464IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker =VHVL.F2.high.F03_Vh/Vl_VH105-VL43_disulfidel; X = CTSL1-1) ACP465mIgG1_Fc-X-IL2-LX-Blocker_(Blocker = VHVL.F2.high.A02_Vh\Vl_A46S; X =CTSL1-1) ACP466 mIgG1_Fc-X-IL2-LX-Blocker_(Blocker =VHVL.F2.high.F03_Vh\Vl; X = CTSL1-1) ACP467mIgG1_Fc-X-IL2-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh/Vl_A46S_VH44-VL100_disulfide; X = CTSL1-1) ACP468mIgG1_Fc-X-IL2-LX-blocker_(Blocker =VHVL.F2.high.A02_Vh/Vl_VH105-VL43_disulfidel; X = CTSL1-1) ACP469mIgG1_Fc-X-IL2-LX-blocker_(Blocker =VHVL.F2.high.F03_Vh/Vl_VH44-VL100_disulfidel; X = CTSL1-1) ACP470mIgG1_Fc-X-IL2-LX-blocker_(Blocker =VHVL.F2.high.F03_Vh/Vl_VH105-VL43_disulfidel; X = CTSL1-1) ACP471mIgG1_Fc-X-IL2-LX-Heavy_blocker_Fab_(Blocker = MT204_VH-CH1; X =CTSL1-1)

SEQUENCE TABLE SEQ ID NO. Name Sequence 1 HumanMYRMQLLSCI ALSLALVTNS APTSSSTKKT QLQLEHLLLD LQMILNGINN IL-2YKNPKLTRML TFKFYMPKKA TELKHLQCLE EELKPLEEVL NLAQSKNFHLRPRDLISNIN VIVLELKGSE TTFMCEYADE TATIVEFLNR WITFCQSIISTLT 2 HumanMKWVTFISLL FLFSSAYSRG VFRRDAHKSE VAHRFKDLGE ENFKALVLIA serumFAQYLQQCPF EDHVKLVNEV TEFAKTCVAD ESAENCDKSL HTLFGDKLCT albuminVATLRETYGE MADCCAKQEP ERNECFLQHK DDNPNLPRLV RPEVDVMCTAFHDNEETFLK KYLYEIARRH PYFYAPELLF FAKRYKAAFT ECCQAADKAACLLPKLDELR DEGKASSAKQ GLKCASLQKF GERAFKAWAV ARLSQRFPKAEFAEVSKLVT DLTKVHTECC HGDLLECADD RADLAKYICE NQDSISSKLKECCEKPLLEK SHCIAEVEND EMPADLPSLA ADFVGSKDVC KNYAEAKDVFLGMFLYEYAR RHPDYSVVLL LRLAKTYETT LEKCCAAADP HECYAKVFDEFKPLVEEPQN LIKQNCELFE QLGEYKFQNA LLVRYTKKVP QVSTPTLVEVSRNLGKVGSK CCKHPEAKRM PCAEDCLSVF LNQLCVLHEK TPVSDRVTKCCTESLVNGRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTALVELVKHK PKATKEQLKAVMDDFAAFVEKCCKADDKET CFAEEGKKLVAASQAALGL 45 ACP12QVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRG (IL2GTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKG fusionTQVTVSSggggsggggsggggsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqprotein)cleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 46 ACP13QVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRG (IL2GTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKG fusionTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAW protein)VRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH 47 ACP14 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSS (IL2SYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYW fusionGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNV protein)GTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTV SSHHHHHH 48ACP15 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSS (IL2SYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYW fusionGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNV protein)GTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH 49 ACP16aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdli(IL2sninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGfusion LVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESV protein)KGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKV EIKHHHHHH 50ACP17 QVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRG (IL2GTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKG fusionTQVTVSSggggsggggsggggsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqprotein)cleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 51 ACP18QVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRG (IL2GTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKG fusionTQVTVSSggggsggggsggggsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqprotein)cleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpgpagmkglpgsDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKH HHHHH 52 ACP19aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdli(IL2sninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSggggsggggsggggsfusion ggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKprotein) GLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKGTQVTVSSHHHHHH** 53 ACP20aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdli(IL2sninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGfusion LVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVR protein)GRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 54 ACP21aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdli(IL2sninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSggggsggggsggggsfusion ggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKprotein) GLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 55 ACP22aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdli(IL2sninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSggggsggggsggggsfusion ggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKprotein) GLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKGTQVTVSSHHHHHH 56 ACP23QVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYRQTPGKQREFVAIINSV (IL2GSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAVYVCNRNFDRIYWGQG fusionTQVTVSSSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSY protein)TLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH 57 ACP24EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSS (IL2SYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYW fusionGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNV protein)GTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH 58 ACP25EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSS (IL2SYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYW fusionGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNV protein)GTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH 59 ACP26QVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRG (IL2GTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKG fusionTQVTVSSggggsggggsggggsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqprotein)cleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsQVQLQQSGAELVRPGTSVKVSCKASGYAFTNYLIEWVKQRPGQGLEWIGVINPGSGGTNYNEKFKGKATLTADKSSSTAYMQLSSLTSDDSAVYFCARWRGDGYYAYFDVWGAGTTVTVSSggggsggggsggggsDIVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYMNWYQQKPGQPPKLLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPYTFGGGTKLEI KHHHHHHEPEA 60ACP27 QVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRG (IL2GTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKG fusionTQVTVSSggggsggggsggggsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqprotein)cleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsDIVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYMNWYQQKPGQPPKLLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPYTFGGGTKLEIKggggsggggsggggsQVQLQQSGAELVRPGTSVKVSCKASGYAFTNYLIEWVKQRPGQGLEWIGVINPGSGGTNYNEKFKGKATLTADKSSSTAYMQLSSLTSDDSAVYFCARWRGDGYYAYFDVWGAGTTVTV SSHHHHHHEPEA 61ACP28aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdli(IL2sninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSggggsggggsggggsfusion ggggsggggsQVQLQQSGAELVRPGTSVKVSCKASGYAFTNYLIEWVKQRPGQGLE protein)WIGVINPGSGGTNYNEKFKGKATLTADKSSSTAYMQLSSLTSDDSAVYFCARWRGDGYYAYFDVWGAGTTVTVSSggggsggggsggggsDIVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYMNWYQQKPGQPPKLLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPYTFGGGTKLEIKggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKGTQVTVSSHHHHHHEPEA 62 ACP29aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdli(IL2sninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSggggsggggsggggsfusion ggggsggggsDIVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYMNWYQQKPGQ protein)PPKLLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPYTFGGGTKLEIKggggsggggsggggsQVQLQQSGAELVRPGTSVKVSCKASGYAFTNYLIEWVKQRPGQGLEWIGVINPGSGGTNYNEKFKGKATLTADKSSSTAYMQLSSLTSDDSAVYFCARWRGDGYYAYFDVWGAGTTVTVSSggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKGTQVTVSSHHHHHHEPEA 63 IL2Ra    10  20   30    40   50MDSYLLMWGL LTFIMVPGCQ AELCDDDPPE IPHATFKAMA YKEGTMLNCE   60  70   80    90   100CKRGFRRIKS GSLYMLCTGN SSHSSWDNQC QCTSSATRNT TKQVTPQPEE  110  120  130   140  150QKERKTTEMQ SPMQPVDQAS LPGHCREPPP WENEATERIY HFVVGQMVYY  160  170  180   190  200QCVQGYRALH RGPAESVCKM THGKTRWTQP QLICTGEMET SQFPGEEKPQ  210  220  230   240  250ASPEGRPESE TSCLVTTTDF QIQTEMAATM ETSIFTTEYQ VAVAGCVFLL   260  270ISVLLLSGLT WQRRQRKSRR TI 64 IL2Rb    10  20   30    40   50MAAPALSWRL PLLILLLPLA TSWASAAVNG TSQFTCFYNS RANISCVWSQ   60  70   80    90   100DGALQDTSCQ VHAWPDRRRW NQTCELLPVS QASWACNLIL GAPDSQKLTT  110  120  130   140    150VDIVTLRVLC REGVRWRVMA IQDFKPFENL RLMAPISLQV VHVETHRCNI  160  170  180   190    200SWEISQASHY FERHLEFEAR TLSPGHTWEE APLLTLKQKQ EWICLETLTP  210  220  230   240    250DTQYEFQVRV KPLQGEFTTW SPWSQPLAFR TKPAALGKDT IPWLGHLLVG  260  270  280   290    300LSGAFGFIIL VYLLINCRNT GPWLKKVLKC NTPDPSKFFS QLSSEHGGDV  310  320  330   340    350QKWLSSPFPS SSFSPGGLAP EISPLEVLER DKVTQLLLQQ DKVPEPASLS  360  370  380   390    400SNHSLTSCFT NQGYFFFHLP DALEIEACQV YFTYDPYSEE DPDEGVAGAP  410  420  430   440    450TGSSPQPLQP LSGEDDAYCT FPSRDDLLLF SPSLLGGPSP PSTAPGGSGA  460  470  480   490    500GEERMPPSLQ ERVPRDWDPQ PLGPPTPGVP DLVDFQPPPE LVLREAGEEV  510  520  530   540    550PDAGPREGVS FPWSRPPGQG EFRALNARLP LNTDAYLSLQ ELQGQDPTHL V  65 IL2Rg   10  20   30    40    50MLKPSLPFTS LLFLQLPLLG VGLNTTILTP NGNEDTTADF FLTTMPTDSL   60  70   80    90    100SVSTLPLPEV QCFVFNVEYM NCTWNSSSEP QPTNLTLHYW YKNSDNDKVQ  110  120  130   140   150KCSHYLFSEE ITSGCQLQKK EIHLYQTFVV QLQDPREPRR QATQMLKLQN  160  170  180   190   200LVIPWAPENL TLHKLSESQL ELNWNNRFLN HCLEHLVQYR TDWDHSWTEQ  210  220  230   240   250SVDYRHKFSL PSVDGQKRYT FRVRSRFNPL CGSAQHWSEW SHPIHWGSNT  260  270  280   290   300SKENPFLFAL EAVVISVGSM GLIISLLCVY FWLERTMPRI PTLKNLEDLV  310  320  330   340   350TEYHGNFSAW SGVSKGLAES LQPDYSERLC LVSEIPPKGG ALGEGPGASP 360CNQHSPYWAP PCYTLKPET 66 ACP04iwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktliqvkefgdagqytchkggevlshslll(humanlhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyp40/murineeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsp35yfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvIL12sgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmfusionmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhprotein) afstrvvtinrymgylssaHHHHHH 67 ACP05iwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshslll(humanlhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltsvkssrgssdpqgvtcgaatlsaervrgdnkeyp40/murineeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsp35yfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrnlpvIL12atpdpgmfpclhhsqnllravsnmlqkarqtlefypctseeidheditkdktstveaclpleltknesclnsretsfitngsclasfusionrktsfmmalclssiyedlkmyqvefktmnakllmdpkrqifldqnmlavidelmqalnfnsetypqkssleepdfyktkiprotein) klcillhafriravtidrvmsylnasHHHHHH 68 ACP06QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQR (humanPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVT p40/murineVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQA p35PGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAV IL12YYCKTHGSHDNWGQGTMVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAG fusionMKGLPGSiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchprotein)kggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsmllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHEPEA 69 ACP07QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQR (humanPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVT p40/murineVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQA p35PGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAV IL12YYCKTHGSHDNWGQGTMVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAG fusionMKGLPGSiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchprotein)kggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYRQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAVYVCNRNFDRIYWGQG TQVTVSSHHHHHHEPEA70 ACP08 QVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYRQTPGKQREFVAIINSV (humanGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAVYVCNRNFDRIYWGQG p40/murineTQVTVSSggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWY p35QQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSY IL12DRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAA fusionSGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKN protein)TLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVT VSSHHHHHHEPEA 71ACP09 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGS (humanGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGT p40/murineLVTVSSggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQ p35QLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYD IL12RYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAAS fusionGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNT protein)LYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaHHHHHHEPEA 72 ACP10EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGS (humanGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGT p40/murineLVTVSSSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgp35sgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsIL12vkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdfusionppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryysssprotein)wsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHHEPEA 73 ACP11iwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshslll(humanlhkkedgiwstdilkdqkepknktftlrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyp40/murineeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsp35yfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvIL12sgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmfusionmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhprotein)afstryvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKWYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHEIREIHHEPEA 74 IL12 p40        10         20         30         40         50 humanMCHQQLVISW FSLVFLASPL VAIWELKKDY YVVELDWYPD APGEMVVLTC (Uniprot        60         70         80         90        100 AccessionDTPEEDGITW TLDQSSEVLG SGKTLTIQVK EFGDAGQYTC HKGGEVLSHS No.       110        120        130        140        150 P29460)LLLLHKKEDG IWSTDILKDQ KEPKNKTFLR CEAKNYSGRF TCWWLTTIST       160        170        180        190       200DLTFSVKSSR GSSDPQGVTC GAATLSAERV RGDNKEYEYS VECQEDSACP       210        220        230        240        250AAEESLPIEV MVDAVHKLKY ENYTSSFFIR DIIKPDPPKN LQLKPLKNSR       260        270        280        290        300QVEVSWEYPD TWSTPHSYFS LTFCVQVQGK SKREKKDRVF TDKTSATVIC       310        320 RKNASISVRA QDRYYSSSWS EWASVPCS 75 IL12 p35        10         20         30         40         50 mouseMCQSRYLLFL ATLALLNHLS LARVIPVSGP ARCLSQSRNL LKTTDDMVKT (Uniprot        60         70         80         90        100 AccessionAREKLKHYSC TAEDIDHEDI TRDQTSTLKT CLPLELHKNE SCLATRETSS No.       110        120        130        140        150 P43431)TTRGSCLPPQ KTSLMMTLCL GSIYEDLKMY QTEFQAINAA LQNHNHQQII       160        170        180        190       200LDKGMLVAID ELMQSLNHNG ETLRQKPPVG EADPYRVKMK LCILLHAFST        210RVVTINRVMG YLSSA 76 IL12Rb-        10         20         30         40         50 2

 

 

 

 

        60         70         80         90        100

 

 

 

 

       110        120        130        140        150

 

 

 

 

       160        170        180        190       200

 

 

 

 

       210        220        230        240        250

 

 

 

 

       260        270        280        290        300

 

 

 

 

       310        320        330        340        350

 

 

 

 

       360        370        380        390        400

 

 

 

 

       410        420        430        440        450

 

 

 

 

       460        470        480        490        500

 

 

 

 

       510        520        530        540        550

 

 

 

 

       560        570        580        590        600

 

 

 

 

       610        620        630        640        650

 

 

 

 

       660        670        680        690        700

 

 

 

 

       710        720        730        740        750

 

 

 

 

       760        770        780        790        800

 

 

 

 

       810        820        830        840        850

 

 

 

 

       860

 ML 77 IL12Rb-         10         20         30         40         50 1MEPLVTWVVP LLFLFLLSRQ GAACRISECC FQDPPYPDAD SGSASGPRDL        60         70         80         90        100RCYRISSDRY ECSWQYEGPT AGVSHFLRCC LSSGRCCYFA AGSATRLQFS       110        120        130        140        150DQAGVSVLYT VTLWVESWAR NQTEKSPEVT LQLYNSVKYE PPLGDIKVSK       160        170        180        190        200LAGQLRMEWE TPDNQVGAEV QFRHRIPSSP WKLGDCGPQD DDTESCLCPL       210        220        230        240        250EMNVAQEFQL RRRQLGSQGS SWSKWSSPVC VPPENPPQPQ VRFSVEQLGQ       260        270        280        290        300DGRRRLILKE QPTQLELPEG CQGLAPGTEV TYRLQLHMLS CPCKAKATRT       310        320        330        340        350LHLGKMPYLS GAAYNVAVIS SNQFGPGLNQ TWHTPADTHT EPVALNISVG       360        370        380        390        400INGTTMYWPA RAQSMTYCIE WQPVGQDGGL ATCSLTAPQD PDPAGMATYS       410        420        430        440        450WSRESGAMGQ EKCYYITIFA SAHPEKLTLW STVLSTYHFG GNASAAGTPH       460        470        480        490        500HVSVKNHSLD SVSVDWAPSL LSTCPGVLKE YVVRCRDEDS KQVSEHPVQP       510        520        530        540        550TETQVTLSGL RAGVYTVQV RADTAWLRGV WSQPQRFSIE VQVSDWLIFF       560        570        580        590        600ASLGSFLSIL LVGVLGYLGL NRAARHLCPP LPTPCASSAI EFPGGKETWQ       610        620        630        640        650WINPVDFQEE ASLQEALVVE MSWDKGERTE PLEKTELPEG APELALDTEL        660SLEDGDRCKA KM 78 IL-12        10         20         30         40         50 p35MCHQQLVISW FSLVFLASPL VAIWELKKDV YVVELDWYPD APGEMVVLTC human        60         70         80         90        100 (UniprotDTPEEDGITW TLDQSSEVLG SGKTLTIQVK EFGDAGQYTC HKGGEVLSHS accession       110        120        130        140        150 no.LLLLHKKEDG IWSTDILKDQ KEPKNKTFLR CEAKNYSGRF TCWWLTTIST P29459)       160        170        180        190        200DLTFSVKSSR GSSDPQGVTC GAATLSAERV RGDNKEYEYS VECQEDSACP       210        220        230        240        250AAEESLPIEV MVDAVHKLKY ENYTSSFFIR DIIKPDPPKN LQLKPLKNSR       260        270        280        290        300QVEVSWEYPD TWSTPHSYFS LTFCVQVQGK SKREKKDRVF TDKTSATVIC       310        320        330 RKNASISVRA QDRYYSSSWS EWASVPCS 79 IL-12        10         20         30         40         50 p40MCPQKLTISW FAIVLLVSPL MAMWELEKDV YVVEVDWTPD APGETVNLTC mouse        60         70         80         90        100 (UniprotDTPEEDGITW TSDQRHGVIG SGKTLTITVK EFLDAGQYTC HKGGETLSHS accession       110        120        130        140        150 no.HLLLHKKENG IWSTEILKNF KNKTFLKCEA PNYSGRFTCS WLVQRNMDLK P43432)       160        170        180        190        200FNIKSSSSSP DSRAVTCGMA SLSAEKVTLD QRDYEKYSVS CQEDVTCPTA       210        220        230        240        250EETLPIELAL EARQQNKYEN YSTSFFIRDI IKPDPPKNLQ MKPLKNSQVE       260        270        280        290        300VSWEYPDSWS TPHSYFSLKF FVRIQRKKEK MKETEEGCNQ KGAFLVEKTS       310        320        330 TEVQCKGGNV CVQAQDRYYN SSCSKWACVP CRVRS80 ACP01 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGS (mouseGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGT IFNgLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisffusionylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGprotein) GPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 81 ACP02EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGS (mouseGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGT IFNgLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisffusionylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGprotein)GPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 82 ACP03EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGS (mouseGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGT IFNgLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisffusionylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcgggprotein)gsggggsggggshgtviesleslnnyfnssgidveekslfidiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGT LVTVSSHHHHHH 83Human         10         20         30         40         50 IFN-gMKYTSYILAF QLCIVLGSLG CYCQDPYVKE AENLKKYFNA GHSDVADNGT (Uniprot        60         70         80         90        100 AccessionLFLGILKNWK EESDRKIMQS QIVSFYFKLF KNFKDDQSIQ KSVETIKEDM No.       110        120        130        140        150 P01579)NVKFFNSNKK KRDDFEKLTN YSVTDLNVQR KAIHELIQVM AELSPAAKTG        160KRKRSQMLFR GRRASQ 84 Mouse        10         20         30         40         50 IFN-gMNATHCILAL QLFLMAVSGC YCHGTVIESL ESLNNYFNSS GIDVEEKSLF (Uniprot        60         70         80         90        100 AccessionLDIWRNWQKD GDMKILQSQI ISFYLRLFEV LKDNQAISNN ISVIESHLIT No.       110        120        130        140        150 P01580)TFFSNSKAKK DAFMSIAKFE VNNPQVQRQA FNELIRVVHQ LLPESSLRKR KRSRC 85 ACP30mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ (mouseAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV IFNgYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslflfusiondiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelprotein) irvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHH H 86 ACP31EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGS (mouseGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGT IFNa1LVTVSSSGGPGPAGMKGLPGScdlpqthnlrnkraltllvqmrrlsplsclkdrkdfgfpqekvdaqqikkafusionqaipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfhritvylrekkhprotein)spcawevvraevwralsssanvlgrlreekSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHEPEA 87 ACP32EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGS (mouseGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGT IFNa1LVTVSSSGGPGPAGMKGLPGScdlpqthnlrnkraltllvqmttlsplsclkdrkdfgfpqekvdaqqikkafusionqaipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfhritvylrekkhprotein) spcawevvraevwralsssanvSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHEPEA 88 IFNgR1        10         20         30         40         50MALLFLLPLV MQGVSRAEMG TADLGPSSVP TPINVTIESY NMNPIVYWEY        60         70         80         90        100QIMPQVPVFT VEVKNYGVKN SEWIDACINI SHHYCNISDH VGDPSNSLWV       110        120        130        140        150RVKARVGQKE SAYAKSEEFA YCRDGKIGPP KLDIRKEEKQ IMIDIFHPSV       160        170        180        190        200FVNGDEQEVD YDPEITCYIR VYNVYVRMNG SEIQYKILTQ KEDDCDEIQC       210        220        230        240        250QLAIPVSSLN SQYCVSAEGV LHVWGVTTEK SKEVCITIFN SSIKGSLWIP       260        270        280        290        300VVAALLLFLV LSLVFICFYI EKINPLKEKS IILPKSLISV VRSATLETKP       310        320        330        340        350ESKYVSLITS YQPFSLEKEV VCEEPLSPAT VPGMHIEDNP GKVEHTEELS       360        370        380        390        400SIIEVVTIEE NIPDVVPGSH LTPIERESSS PLSSNQSEPG SIALNSYHSR       410        420        430        440        450NCSESDHSRN GPDTDSSCLE SHSSLSDSEP PPNNKGEIKT EGQELITVIK       460        470        480APTSFGYDKP HVLVDLLVDD SGKESLIGYR PTEDSKEFS 89 IFNgR2        10         20         30         40         50MRPTLLWSLL LLLGVFAAAA AAPPDPLSQL PAPQHPKIRL YNAEQVLSWE        60         70         80         90        100PVALSNSTRP VVYQVQFKYT DSKWFIADIM SIGVNCTQIT ATECDETAAS       110        120        130        140        150PSAGFPMDFN VTLRLRAELG ALHSAWVTMP WFQHYRNVTV GPPENIEVTP       160        170        180        190        200GEGSLIIRFS SPFDIADTST AFFCYYVHYW EKGGIQQVKG PFRSNSISLD       210        220        230        240        250NLKPSRVYCL QVQAQLLNNK SNIFRVGHLS NISCYETMAD ASTELQQVIT       260        270        280        290        300ISVGTFSLLS WLAGACFFLV LKYRGLIKYW FHTPPSIPLQ IEEYLKDPTQ       310        320        330PILEALDKDS SPKDDVWDSV SIISFPEKEQ EDVLQTL 90 ACP51QVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRG MouseGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKG IFGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSW fusionVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPED proteinTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 91 ACP52EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGS MouseGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGT IFGLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisffusionylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGprotein GPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKG TQVTVSSHHHHHH 92ACP53eahkseiahryndlgeqhfkglvliafsqylqkcsydehaklvqevtdfaktcvadesaancdkslhtlfgdklcaipnlrenMouseygeladcctkqepemecflqhkddnpslppferpeaeamctsfkenpttfmghylhevarrhpyfyapellyyaeqyneiIFGltqccaeadkescltpkldgvkekalvssvrqrmkcssmqkfgerafkawavarlsqtfpnadfaeitklatdltkvnkeccfusionhgdllecaddraelakymcenqatissklqtccdkpllkkahclsevehdtmpadlpaiaadfvedqevcknyaeakdvflproteingtflyeysrrhpdysyslllrlakkyeatlekccaeanppacygtvlaefqplveepknlvktncdlyeklgeygfqnailvrytqkapqvstptiveaarnlgrvgtkcctlpedqrlpcvedylsailnrvcllhektpvsehvtkccsgslverrpcfsaltvdetyvpkefkaetftfhsdictlpekekqikkqtalaelvkhkpkataeqlktvmddfaqfldtcckaadkdtcfstegpnlvtrckdalaSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSeahkseiahryndlgeqhfkglvliafsqylqkcsydehaklvqevtdfaktcvadesaancdkslhtlfgdklcaipnlrenygeladcctkqepernecflqhkddnpslppferpeaeamctsfkenpttfmghylhevarrhpyfyapellyyaeqyneiltqccaeadkescltpkldgvkekalvssvrqrmkcssmqkfgerafkawavarlsqtfpnadfaeitklatdltkvnkecchgdllecaddraelakymcenqatissklqtccdkpllkkahclsevehdtmpadlpaiaadfvedqevcknyaeakdvflgtflyeysrrhpdysyslllrlakkyeatlekccaeanppacygtvlaefqplveepknlvktncdlyeklgeygfqnailvrytqkapqvstptlveaarnlgrvgtkcctlpedqrlpcvedylsailnrycllhektpvsehvtkccsgslverrpcfsaltvdetyvpkefkaetftfhsdictlpekekqikkqtalaelvkhkpkataeqlktvmddfaqfldtcckaadkdtcfstegpnlvtrckdalaHHHHHH 93 ACP54eahkseiahryndlgeqhfkglvliafsqylqkcsydehaklvqevtdfaktcvadesaancdkslhtlfgdklcaipnlrenMouseygeladcctkqepemecflqhkddnpslppferpeaeamctsfkenpttfmghylhevarrhpyfyapellyyaeqyneiIFGltqccaeadkescltpkldgvkekalvssvrqrmkcssmqkfgerafkawavarlsqtfpnadfaeitklatdltkvnkeccfusionhgdllecaddraelakymcenqatissklqtccdkpllkkahclsevehdtmpadlpaiaadfvedqevcknyaeakdvflproteingtflyeysrrhpdysvslllrlakkyeatlekccaeanppacygtvlaefqplveepknlvktncdlyeklgeygfqnailvrytqkapqvstptlveaarnlgrvgtkcctlpedqrlpcvedylsailnrvcllhektpvsehvtkccsgslverrpcfsaltvdetyvpkefkaetftfhsdictlpekekqikkqtalaelvkhkpkataeqlktvmddfaqfldtcckaadkdtcfstegpnlvtrckdalaSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcggggsggggsggggshgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSeahkseiahryndlgeqhfkglvliafsqylqkcsydehaklvqevtdfaktcvadesaancdkslhtlfgdklcaipnlrenygeladcctkqepernecflqhkddnpslppferpeaeamctsfkenpttfmghylhevarrhpyfyapellyyaeqyneiltqccaeadkescltpkldgvkekalvssvrqrmkcssmqkfgerafkawavarlsqtfpnadfaeitklatdltkvnkecchgdllecaddraelakymcenqatissklqtccdkpllkkahclsevehdtmpadlpaiaadfvedqevcknyaeakdvflgtflyeysrrhpdysyslllrlakkyeatlekccaeanppacygtvlaefqplveepknlvktncdlyeklgeygfqnailvrytqkapqvstptlveaarnlgrvgtkcctlpedqrlpcvedylsailnrycllhektpvsehvtkccsgslverrpcfsaltvdetyvpkefkaetftfhsdictlpekekqikkqtalaelvkhkpkataeqlktvmddfaqfldtcckaadkdtcfstegpnlvtrckdalaHHHHHH 94 ACP50mdmrvpaqllgllllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQA MousePGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYY IFGCNALYGTDYWGKGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNSLRLSC fusionAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAK proteinTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcggggsggggsggggshgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 95 ACP55mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ MouseAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV IFGYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslflfusiondiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelprotein irvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHH H 96 ACP56mdmrvpaqllgllllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYR MouseQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAV IFGYVCNRNFDRIYWGQGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNSLRLS fusionCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNA proteinKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSH HHHHHEPEA 97ACP57 mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQMouse APGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV IFGYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslflfusiondiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelprotein irvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYRQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAVYVCNRNFDRIYWGQGTQVTVSSH HHHHHEPEA 98 ACP58mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ MouseAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV IFGYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslflfusiondiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelproteinirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKGTQVTVSSHHHHHHEPEA 99 ACP59mdmrvpaqllgllllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYR MouseQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAV IFGYVCNRNFDRIYWGQGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNSLRLS fusionCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNA proteinKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHEPE A 100 ACP60mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ MouseAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV IFGYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslflfusiondiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelproteinirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYRQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAVYVCNRNFDRIYWGQGTQVTVSSHHHHHHEPEA 101 ACP61mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ MouseAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV IFGYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslflfusiondiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelproteinirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGVGAFRPYRKHEWGQGTLVTVSRggggsggggsggggsSSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTTTGAQAEDEADYYCNSSPFEHNLVVFGGGTKLTVLHHHHHHEPEA 102 ACP63mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQ Anti-FNAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAV CGS-2YYCARGVGAFRPYRKHEWGQGTLVTVSRggggsggggsggggsSSELTQDPAVSVAL scFvGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTTTGAQAEDEADYYCNSSPFEHNLVVFGGGTKLTVLHHHHHHEPEA 103 ACP69mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ MouseAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV IFGYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslflfusiondiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelprotein irvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcHHHHHHEPEA 104 ACP70mdmrvpaqllgllllwlrgarchgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdMousenqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGIFG MKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLE fusionWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGS proteinLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHEPEA 105 ACP71mdmrvpaqllgllllwlrgarchgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdMousenqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGIFG MKGLPGSEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVT fusionDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNEC proteinFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALASGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALAHHH HHHEPEA 106 ACP72mdmrvpaqllgllllwlrgarcEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHA MouseKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTK IFGQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHP fusionYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCS proteinSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALASGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALASGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcHHHHHHEPEA 107 ACP73mdmrvpaqllgllllwlrgarcEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHA MouseKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTK IFGQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHP fusionYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCS proteinSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALASGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALASGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDAL AHHHHHHEPEA 108ACP74 mdmrvpaqllgllllwlrgarcEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAMouse KLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTK IFGQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHP fusionYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCS proteinSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALASGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSggggsEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALAggggsSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVT RCKDALAHHHHHHEPEA109 ACP75 mdmrvpaqllgllllwlrgarcEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAMouse KLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTK IFGQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHP fusionYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCS proteinSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALASGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSggggsggggsEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALAggggsggggsSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALAHHHHHHEPEA 110 ACP78mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ MouseAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV IFGYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggshgtviesleslnnyfnssgidveekslfldiwrnfusionwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhproteinqllpesslrkrkrsrcggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggshgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHEIHRHEPEA 111 ACP134mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ MouseAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV IFGYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslflfuisiondiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelprotein irvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYRQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAVYVCNRNFDRIYWGQGTQVTVSSHHHHHHEPEA 112 ACP135mdmrvpaqllgllllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYR MouseQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAV IFGYVCNRNFDRIYWGQGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNSLRLS fusionCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNA proteinKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHEPEA 113 ACP34mdmrvpaqllgllllwlrgarcrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelMousehknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhnIL-12getlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSmwelekdvyvvfusionevdwtpdapgetvnltcdtpeedditwtsdqrhgvigsgktltitvkefldagqytchkggetlshshlllhkkengiwsteilproteinknfknktflkceapnysgrftcswlvqrnmdlkfnikssssspdsravtcgmaslsaekvtldqrdyekysvscqedvtcptaeetlpielalearqqnkyenystsffirdiikpdppknlqmkplknsqvevsweypdswstphsyfslkffvriqrkkekmketeegcnqkgaflvektstevqckggnvcvqaqdryynsscskwacvpcrvrsHHHHHH 114 ACP35mdmrvpaqllgllllwlrgarcrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelMousehknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhnIL-12getlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaggggsggggsggggsSGGPGPAGMKGLPfusionGSggggsggggsggggsmwelekdvyvvevdwtpdapgetvnltcdtpeedditwtsdqrhgvigsgktltitvkefldproteinagqytchkggetlshshlllhkkengiwsteilknfknktflkceapnysgrftcswlvqrnmdlkfnikssssspdsravtcgmaslsaekvtldqrdyekysvscqedvtcptaeetlpielalearqqnkyenystsffirdiikpdppknlqmkplknsqvevsweypdswstphsyfslkffvriqrkkekmketeegcnqkgaflvektstevqckggnvcvqaqdryynsscskwacvpcrvrsHHHHHH 115 ACP36mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ MouseAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV IL-12YYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSmwelekdvyvvevdwtpdapgetv fusionnltcdtpeedditwtsdqrhgvigsgktltitvkefldagqytchkggetlshshlllhkkengiwsteilknfknktflkceapproteinnysgrftcswlvqrnmdlkfnikssssspdsravtcgmaslsaekvtldqrdyekysvscqedvtcptaeetlpielalearqqnkyenystsffirdiikpdppknlqmkplknsqvevsweypdswstphsyfslkffvriqrkkekmketeegcnqkgaflvektstevqckggnvcvqaqdryynsscskwacypcrvrsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 116 ACP37mdmrvpaqllgllllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQA MousePGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYY IL-12CNALYGTDYWGKGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNSLRLSC fusionAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAK proteinTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSmwelekdvyvvevdwtpdapgetvnltcdtpeedditwtsdqrhgvigsgktltitvkefldagqytchkggetlshshlllhkkengiwsteilknfknktflkceapnysgrftcswlyqrnmdlkfnikssssspdsravtcgmaslsaekvtldqrdyekysvscqedvtcptaeetlpielalearqqnkyenystsffirdiikpdppknlqmkplknsqveysweypdswstphsyfslkffvriqrkkekmketeegcnqkgaflvektstevqckggnvcvqaqdryynsscskwacvpcrvrsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 117 ACP79mdmrvpaqllgllllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQA MousePGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYY IL-12CNALYGTDYWGKGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNSLRLSC fusionAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAK proteinTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSmwelekdvyvvevdwtpdapgetvnltcdtpeedditwtsdqrhgvigsgktltitykefldagqytchkggetlshshlllhkkengiwsteilknfknktflkceapnysgrftcswlvqrnmdlkfnikssssspdsravtcgmaslsaekvtldqrdyekysvscqedvtcptaeetlpielalearqqnkyenystsffirdiikpdppknlqmkplknsqvevsweypdswstphsyfslkffvriqrkkekmketeegcnqkgaflvektstevqckggnvcvqaqdryynsscskwacvpcrvrsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 118 ACP80mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ MouseAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV IL-12YYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSmwelekdvyvvevdwtpdapgetv fusionnltcdtpeedditwtsdqrhgvigsgktltitvkefldagqytchkggetlshshlllhkkengiwsteilknfknktflkceapproteinnysgrftcswlvqrnmdlkfnikssssspdsravtcgmaslsaekvtldqrdyekysvscqedvtcptaeetlpielalearqqnkyenystsffirdiikpdppknlqmkplknsqvevsweypdswstphsyfslkffvriqrkkekmketeegcnqkgaflvektstevqckggnvcvqaqdryynsscskwacvpcrvrsggggsggggsggggsrvipvsgparclsqsrnllkttddmyktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKGTQVTVSSHHHHHH 119 ACP91mdmrvpaqllgllllwlrgarciwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkeChimericfgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpIL-12qgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplkfusionnsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsproteinggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetltrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaggggsggggsggggsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHEP EA 120 ACP136mdmrvpaqllgllllwlrgarciwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkeChimericfgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpIL-12qgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplkfusionnsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsproteinggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHREIREIHEPEA 121 ACP138mdmrvpaqllgllllwlrgarciwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkeChimericfgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpIL-12qgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplkfusionnsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsproteinggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYRQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAVYVCNRNFDRIYWGQGTQVTVSSHEIREIHHEPEA 122 ACP139mdmrvpaqllgllllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYR ChimericQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAV IL-12YVCNRNFDRIYWGQGTQVTVSSggggsggggsggggsiwelkkdvyvveldwypdapgemvvltcdfusiontpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknproteinysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHEPEA 123 ACP140mdmrvpaqllgllllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYR ChimericQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAV IL-12YVCNRNFDRIYWGQGTQVTVSSSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapge fusionmvvltcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktproteinflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHEPEA 124 ACP38mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeeIL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKfusion GLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWV proteinAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGK GTQVTVSSHHHHHH 125ACP39 mdmrvpaqllgllllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAIL-2 PGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYY fusionCNALYGTDYWGKGTQVTVSSSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSL proteinRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltffympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH** 126 ACP40mdmrvpaqllgllllwlrgarcelcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqIL-2cqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyrfusionalhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsclvtttdfqiqtemaatmetsiftteyqproteinggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH 127 ACP41mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeeIL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKfusionGLPGSggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgsproteinlymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsclvtttdfqiqtemaatmetsiftteyqHHHHHH 128 ACP42mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ IL-2APGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV fusionYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrproteingfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsclvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH 129 ACP43mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeeIL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKfusionGLPGSggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgsproteinlymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsclvtttdfqiqtemaatmetsiftteyqggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 130 ACP44mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeeIL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKfusionGLPGSggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgsproteinlymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsclvtttdfqiqtemaatmetsiftteyqSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSFIRREIREI 131 ACP45mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ IL-2APGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV fusionYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGS proteinLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH 132 ACP46mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeeIL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKfusion GLPGSggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFprotein TFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpgpagmkglpgsDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKGTQVTVSSHHHHHH 133 ACP47mdmrvpaqllgllllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQA IL-2PGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYY fusionCNALYGTDYWGKGTQVTVSSggggsggggsggggsaptssstkktqlqlehllldlqmilnginnyknpkproteinltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 134 ACP48mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeeIL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKfusion GLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWV proteinAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 135 ACP49mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeeIL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKfusion GLPGSggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFprotein TFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 136 ACP92mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ IL-2APGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV fusionYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginproteinnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 137 ACP93mdmrvpaqllgllllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQA IL-2PGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYY fusionCNALYGTDYWGKGTQVTVSSgsgsgsgsgsgsgsgsEVQLVESGGGLVQPGNSLRLSC proteinAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSgsgsgsgsgsgsgsgsQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKGTQVTVSSgsgsgsgsgsgsgsgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH 138 ACP94mdmrvpaqllgllllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQA IL-2PGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYY fusionCNALYGTDYWGKGTQVTVSSgsgsgsgsgsgsgsgsEVQLVESGGGLVQPGNSLRLSC proteinAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSgsgsgsgsgsgsgsgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmlafympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH 139 ACP95mdmrvpaqllgllllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQA IL-2PGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYY fusionCNALYGTDYWGKGTQVTVSSgsgsgsgsgsgsgsgsEVQLVESGGGLVQPGNSLRLSC proteinAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH 140 ACP96mdmrvpaqllgllllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQA IL-2PGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYY fusionCNALYGTDYWGKGTQVTVSSSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilngin proteinnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 141 ACP97mdmrvpaqllgllllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQA IL-2PGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYY fusionCNALYGTDYWGKGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNSLRLSC proteinAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHH H 142 ACP99mdmrvpaqllgllllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQA IL-2PGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYY fusionCNALYGTDYWGKGTQVTVSSggggsggggsggggsaptssstkktqlqlehllldlqmilnginnyknpkproteinltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 143 ACP100mdmrvpaqllgllllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQA IL-2PGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYY fusionCNALYGTDYWGKGTQVTVSSggggsggggsggggsaptssstkktqlqlehllldlqmilnginnyknpkproteinltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwtfcqsiistltHHHHHH 144 ACP101mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeeIL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKfusion GLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWV proteinSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 145 ACP102mdmrvpaqllgllllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQA IL-2PGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYY fusionCNALYGTDYWGKGTQVTVSSSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilngin proteinnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 146 ACP103mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeeIL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKfusion GLPGSggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFprotein TFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYRQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAVYVCNRNFDRIYWGQGTQVTVSSHHHHHH 147 ACP104mdmrvpaqllgllllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYR IL-2QTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAV fusionYVCNRNFDRIYWGQGTQVTVSSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkproteinatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 148 ACP105mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQ IL-2APGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVY fusionYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSAS proteinVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYRQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAVYVCNRNFDRIYWGQGTQVTVSSHHHHHH 149 ACP106mdmrvpaqllgllllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYR IL-2QTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAV fusionYVCNRNFDRIYWGQGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNSLRLS proteinCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH 150ACP107 mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQIL-2 APGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVY fusionYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSAS proteinVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYRQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAVYVCNRNFDRIYWGQGTQVTVSSHHHHHH 151 ACP108mdmrvpaqllgllllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQA IL-2PGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYY fusionCNALYGTDYWGKGTQVTVSSggggsggggsggggsaptssstkktqlqlehllldlqmilnginnyknpkproteinltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSrgetgpaaPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 152 ACP117mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQ Anti-FNAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAV CGS-2YYCARGVGAFRPYRKHEWGQGTLVTVSRggggsggggsggggsSSELTQDPAVSVAL scFvGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTTTGAQAEDEADYYCNSSPFEHNLVVFGGGTKLTVLHHHHHHEPEA 153 ACP118mdmrvpaqllgllllwlrgarcQVQLQQSGAELVRPGTSVKVSCKASGYAFTNYLIEWVKQ NARA1RPGQGLEWIGVINPGSGGTNYNEKFKGKATLTADKSSSTAYMQLSSLTSDDSAV Vh/V1YFCARWRGDGYYAYFDVWGAGTTVTVSSggggsggggsggggsDIVLTQSPASLAVS non-LGQRATISCKASQSVDYDGDSYMNWYQQKPGQPPKLLIYAASNLESGIPARFSG cleavableSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPYTFGGGTKLEIKHHHHHHEPEA 154 ACP119mdmrvpaqllgllllwlrgarcQVQLQQSGAELVRPGTSVKVSCKASGYAFTNYLIEWVKQ NARA1RPGQGLEWIGVINPGSGGTNYNEKFKGKATLTADKSSSTAYMQLSSLTSDDSAV Vh/V1YFCARWRGDGYYAYFDVWGAGTTVTVSSSGGPGPAGMKGLPGSDIVLTQSPAS cleavableLAVSLGQRATISCKASQSVDYDGDSYMNWYQQKPGQPPKLLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPYTFGGGTKLEIKHHHHHHEP EA 155 ACP120mdmrvpaqllgllllwlrgarcDIVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYMNW NARA1YQQKPGQPPKLLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQS V1/VhNEDPYTFGGGTKLEIKggggsggggsggggsQVQLQQSGAELVRPGTSVKVSCKASGY non-AFTNYLIEWVKQRPGQGLEWIGVINPGSGGTNYNEKFKGKATLTADKSSSTAYM cleavableQLSSLTSDDSAVYFCARWRGDGYYAYFDVWGAGTTVTVSSHHHHHHEPEA 156 ACP121mdmrvpaqllgllllwlrgarcDIVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYMNW NARA1YQQKPGQPPKLLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQS V1/VhNEDPYTFGGGTKLEIKSGGPGPAGMKGLPGSQVQLQQSGAELVRPGTSVKVSCK cleavableASGYAFTNYLIEWVKQRPGQGLEWIGVINPGSGGTNYNEKFKGKATLTADKSSSTAYMQLSSLTSDDSAVYFCARWRGDGYYAYFDVWGAGTTVTVSSHHHHHHEP EA 157 ACP124mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeeIL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsfusion EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGS proteinGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGT LVTVSSHHHHHHEPEA158 ACP132mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeeIL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsfusiondahksevahrfkdlgeenfkalvliafaqylqqcpfedhvklvnevtefaktcvadesaencdkslhtlfgdklctvatlretyproteingemadccakqepernecflqhkddnpnlprlvrpevdvmctafhdneetflkkylyeiarrhpyfyapellffakrykaafteccqaadkaacllpkldelrdegkassakqrlkcaslqkfgerafkawavarlsqrfpkaefaevsklvtdltkvhtecchgdllecaddradlakyicenqdsissklkeccekpllekshciaevendempadlpslaadfveskdvcknyaeakdvflgmflyeyarrhpdysvvlllrlaktyettlekccaaadphecyakvfdefkplveepqnlikqncelfeqlgeykfqnallvrytkkvpqvstptlvevsrnlgkvgskcckhpeakrmpcaedylsvvlnqlcvlhektpvsdrvtkccteslvnrrpcfsalevdetyvpkefnaetftfhadictlsekerqikkqtalvelvkhkpkatkeqlkavmddfaafvekcckaddketcfaeegkklvaasqaalglHHHHHHEPEA 159 ACP141mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeeIL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsfusiondahksevahrfkdlgeenfkalvliafaqylqqcpfedhvklvnevtefaktcvadesaencdkslhtlfgdklctvatlretyproteingemadccakqepernecflqhkddnpnlprlvrpevdvmctafhdneetflkkylyeiarrhpyfyapellffakrykaafteccqaadkaacllpkldelrdegkassakqrlkcaslqkfgerafkawavarlsqrfpkaefaevsklvtdltkvhtecchgdllecaddradlakyicenqdsissklkeccekpllekshciaevendempadlpslaadfveskdvcknyaeakdvflgmflyeyarrhpdysvvlllrlaktyettlekccaaadphecyakvfdefkplveepqnlikqncelfeqlgeykfqnallvrytkkvpqvstptlvevsrnlgkvgskcckhpeakrmpcaedylsvvlnqlcvlhektpvsdrvtkccteslvnrrpcfsalevdetyvpkefnaetftfhadictlsekerqikkqtalvelvkhkpkatkeqlkavmddfaafvekcckaddketcfaeegkklvaasqaalglHHHHHHEPEA 160 ACP142mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeeIL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKfusionGLPGSdahksevahrfkdlgeenfkalvliafaqylqqcpfedhvklvnevtefaktcvadesaencdkslhtlfgdklctproteinvatlretygemadccakqepernecflqhkddnpnlprlvrpevdvmctafhdneetflkkylyeiarrhpyfyapellffakrykaafteccqaadkaacllpkldelrdegkassakqrlkcaslqkfgerafkawavarlsqrfpkaefaevsklvtdltkvhtecchgdllecaddradlakyicenqdsissklkeccekpllekshciaevendempadlpslaadfveskdvcknyaeakdvflgmflyeyarrhpdysvvlllrlaktyettlekccaaadphecyakvfdefkplveepqnlikqncelfeqlgeykfqnallvrytkkvpqvstptlvevsrnlgkvgskcckhpeakrmpcaedylsvvlnqlcvlhektpvsdrvtkccteslvnrrpcfsalevdetyvpkefnaetftfhadictlsekerqikkqtalvelvkhkpkatkeqlkavmddfaafvekcckaddketcfaeegkklvaasqaalglHHHHHHEPEA 161 ACP144mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeeIL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKfusion GLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWV proteinSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYRQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAVYVCNRNFDRIYWGQGTQVTVSSHHHHHHEPEA 162 ACP145mdmrvpaqllgllllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYR IL-2QTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAV fusionYVCNRNFDRIYWGQGTQVTVSSggggsggggsggggsaptssstkktqlqlehllldlqmilnginnyknproteinpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHHEPEA 163 ACP146mdmrvpaqllgllllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYR IL-2QTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAV fusionYVCNRNFDRIYWGQGTQVTVSSSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilng proteininnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHHEPEA 164 ACP133mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeeIL-2-lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH6xHis (“6xHis” disclosed as SEQ ID NO.: 354) 165 ACP147mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeeIL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKfusion GLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWV proteinSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKGTQVTVSSHHHHHHEPEA 166 ACP148mdmrvpaqllgllllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQA IL-2PGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYY fusionCNALYGTDYWGKGTQVTVSSggggsggggsggggsaptssstkktqlqlehllldlqmilnginnyknpkproteinltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHHEPEA 167 ACP149mdmrvpaqllgllllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQA IL-2PGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYY fusionCNALYGTDYWGKGTQVTVSSSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilngin proteinnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHHEPEA 168 ACP33mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ MouseAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV IFNa-YYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGScdlpqthnlrnkraltllvqmrrlsplscfusionlkdrkdfgfpqekvdaqqikkapipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltproteinqedallavrkyfhritvylrekkhspcawevvraevwralsssanvSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHH HHHHEPEA 169ACP131mdmrvpaqllgllllwlrgarccdlpqthnlrnkraltllvqmrrlsplsclkdrkdfgfpqekvdaqqikkaqaipvlseltqMouseqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfhritvylrekkhspcawevvrIFNa aevwralsssanvlgrlreekHHHHHHEPEA 170 ACP125mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ MouseAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV IFNa-YYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGScdlpqthnlrnkraltllvqmrrlsplscfusionlkdrkdfgfpqekvdaqqikkaqaipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltprotein qedallavrkyfhritvylrekkhspcawevvraevwralsssanvlgrlreekHHHHHHEPEA171 ACP126mdmrvpaqllgllllwlrgarccdlpqthnlrnkraltllvqmrrlsplsclkdrkdfgfpqekvdaqqikkaqaipvlseltqMouseqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfhritvylrekkhspcawevvrIFNa- aevwralsssanvlgrlreekSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASfusion GFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTL proteinYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHEPEA 172 ACP127mdmrvpaqllgllllwlrgarcEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHA MouseKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTK IFNa-QEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHP fusionYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCS proteinSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALASGGPGPAGMKGLPGScdlpqthnlrnkraltllvqmrrlsplsclkdrkdfgfpqekvdaqqikkaqaipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfhritvylrekkhspcawevvraevwralsssanvlgrlreekSGGPGPAGMKGLPGSEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALAHHHHHHEPEA 173 ACP128mdmrvpaqllgllllwlrgarcEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHA MouseKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTK IFNa-QEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHP fusionYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCS proteinSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALASGGPGPAGMKGLPGScdlpqthnlrnkraltllvqmrrlsplsclkdrkdfgfpqekvdaqqikkaqaipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfhritvylrekkhspcawevvraevwralsssanvlgrlreekHHHHHHEPEA 174 ACP129mdmrvpaqllgllllwlrgarccdlpqthnlrnkraltllvqmrrlsplsclkdrkdfgfpqekvdaqqikkaqaipvlseltqMouseqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfhritvylrekkhspcawevvrIFNa- aevwralsssanvlgrlreekSGGPGPAGMKGLPGSEAHKSEIAHRYNDLGEQHFKGLVLIfusion AFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPN proteinLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALAHHHHHHEPEA 175 ACP150mdmrvpaqllgllllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYR MouseQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAV IFNa-YVCNRNFDRIYWGQGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNSLRLS fusionCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNA proteinKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGScdlpqthnlrnkraltllvqmrrlsplsclkdrkdfgfpqekvdaqqikkapipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfhritvylrekkhspcawevvraevwralsssanvlgrlreekSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHEPEA 176 ACP151mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ MouseAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV IFNa-YYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGScdlpqthnlrnkraltllvqmrrlsplscfusionlkdrkdfgfpqekvdaqqikkapipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltproteinqedallavrkyfhritvylrekkhspcawevvraevwralsssanvlgrlreekSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYRQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAVYVCNRNFDRIYWGQGTQVTVSSHHHHHHEPEA 177 ACP152mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ MouseAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV IFNa-YYCTIGGSLSVSSQGTLVTVSSggggsggggsggggscdlpqthnlrnkraltllvqmrrlsplsclkdrkdffusiongfpqekvdaqqikkapipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallaproteinvrkyfhritvylrekkhspcawevvraevwralsssanvlgrlreekggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH EPEA 178 ACP153mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleee(IL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQConju- pgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS gate)GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHHEPEA 179 ACP154mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleee(IL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpPGGPAGIGpConju- gsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS gate)GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpPGGPAGIGpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHHEPEA 180 ACP155mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleee(IL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpALFKSSFPpConju- gsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS gate)GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHHEPEA 181 ACP156mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleee(IL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpPLAQKLKSConju- SpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSI gate)SGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpPLAQKLKSSpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHHEPEA 182 ACP157mdmrvpaqllgllllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleee(IL-2lkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpPGGPAGIGaConju- lfkssfpPLAQKLKSSpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR gate)QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpPGGPAGIGalfkssfpPLAQKLKSSpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHHEPEA 183 Place Hold 184Place Hold 185 Place Hold 186 Place Hold 187 Place Hold 188 Place Hold189 Place Hold 190 Place Hold 191 Blocker 2mdmrvpaqllgllllwlrgarcEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQ (IL2APGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVY blocker)YCARDSNWDALDYWGQGTTVTVSSggggsggggsggggsDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 192 BlockermdmrvpaqllgllllwlrgarcQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQL 12 (IL-12PGTAPKWYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRY blocker)THPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 193 Human_IcdlpqthslgsrrtlmllaqmrrislfsclkdrhdfgfpqeefgnqfqkaetipvlhemiqqifnlfstkdssaawdetlldkfyFNA2btelyqqlndleacviqgvgvtetplmkedsilavrkyfqritlylkekkyspcawevvraeimrsfslstnlqeslrskeHHHHHH** 194 ACP239iwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshsllll-genearthkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssahhhhhh 195 3CYT5_sQVQLQESGGGLVQAGGSLRLSCAASGRTFSSVYDMGWFRQAPGKDREFVARITESARNTRYADSV dAbRGRFTISRDNAKNTVYLQMNNLELEDAAVYYCAADPQTVVVGTPDYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH 196 ACP248QSVLTQPPSVSGAPGQRVTISCtGSsSNIGSNTVKWYQQLPGTAPKLLIYgNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPAyvFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHHR 197 ACP249QSVLTQPPSVSGAPGQRVTISCtGSsSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPAyvFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 198 ACP250QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYaMHWVRQAPGKGLEWVAvIsYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCarHGSHDNWGQGTMVTVSSHHHHHH 199 ACP251QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 200 ACP252QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYAeSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 201 ACP253QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSqTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYeRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 202 ACP254QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSqTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYsRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 203 ACP255QSVLTQPPSVSGAPGQRVTISCSGSeSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 204 ACP256QSVLTQPPSVSGAPGQRVTISCSGSsSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 205 ACP257QSVLTQPPSVSGAPGQRVTISCSGSRSNIGdNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 206 ACP258QSVLTQPPSVSGAPGQRVTISCSGSRSNIGeNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 207 ACP259QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSdTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 208 ACP260QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 209 ACP261QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNdVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 210 ACP262QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVdWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 211 ACP263QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVeWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 212 ACP264QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQdPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 213 ACP265QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQePSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 214 ACP266QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPdGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 215 ACP267QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDeYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 216 ACP268QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTdPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 217 ACP269QSVLTQPPSVSGAPGQRVTISCSGSeSNIGSNTVKWYQQLPGTAPKLLIYYNDQePSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDeYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 218 ACP270QSVLTQPPSVSGAPGQRVTISCSGSeSNIGSNdVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 219 ACP271QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFeSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 220 ACP272QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSeYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 221 ACP273QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSdYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 222 ACP274QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIeYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 223 ACP275QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIdYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 224 ACP276QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNdYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 225 ACP277QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNeYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHEIHHHH 226 ACP278QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVeGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 227 ACP279QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSeDNWGQGTMVTVSSHHHHHH 228 ACP280QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIeYDGSNKYYADSVeGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 229 ACP281QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIeYDGSNKYYADSVeGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSeDNWGQGTMVTVSSHHHHHH 230 ACP282QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHEIREIHH 231 ACP283iwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgtltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcs 232 3TOW6QVQLQESGGGLVQTGGSLRLSCTTSGTIFSGYTMGWYRQAPGEQRELVA 9sdAbVISGGGDTNYADSVKGRFTISRDNTKDTMYLQMNSLKPEDTAVYYCYSREVTPPWKLYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH 233 3TOW85QVQLQESGGGLVQEGGSLRLSCAASERIFSTDVMGWYRQAAEKQRELVAVVSA sdAbRGTTNYLDAVKGRFTISRDNARNTLTLQMNDLKPEDTASYYCYVRETTSPWRIYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH 234 2TOW91QVQLQESGGGLVQAGGSLRLSCAASGSIFSANAMGWYRQAPGKQRELVAVISS sdAbGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCMYSGSYYYTPNDYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH 235 ACP301evqlvesggglvqpggslrlscaasgftfssytlawvrqapgkglewvaaidsssvtvspdtvrgrftisrdnaknslylqmnslraedtavyycardsnwdaldywgqgttvtvssggggsggggsggggsdiqmtqspsslsasvgdrvtitckasqnvgtnvgwyqqkpgkapkaliysasfrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyvtvpytfgggtkveikhhhhhh 236 Hu2TOevqllesggglvqpggslrlscaasGSIFSANAMGwYrqapgkQReLvAVISSGGSTNYAD W91_ASVKGrftisrdnskntVylqmnslraedtavyycMYSGSYYYTPNDYwgqgtlvtvssAAAYPYDVPDYGSHHHHHH** 237 Hu2TOevqllesggglvqpggslrlscaasGSIFSANAMGwYrqapgkgleLvAVISSGGSTNYADSVKGrftW91_B isrdnskntVylqmnslraedtavyycMYSGSYYYTPNDYwgqgtlvtvssAAAYPYDVPDYGSHHHHHH** 238 Hu2TOevqllesggglvqpggslrlscaasGSIFSANAMGwvrqapgkglewvsVISSGGSTNYADSVKGrftisW91_C rdnskntlylqmnslraedtavyycMYSGSYYYTPNDYwgqgtlvtvssAAAYPYDVPDYGSHHHHHH** 239 Hu2TOQvqllesggglyqpggslrlscaasGSIFSANAMGwYrqapgkQReLvAVISSGGSTNYADSVKG W91_DrftisrdnskntVylqmnslraedtavyycMYSGSYYYTPNDYwgqgtlVtVssAAAYPYDVPDYGSHHHHHH** 240 HE_LM_evqLlesggglVqpggslrlscaasgSIfsANamGwYrqapgkgReLvAVissggstNyadsvkgrftisrdnsknt2TOW91 VylqmnslraedtavyycMYSGSYYYTPNDYWgqgtlvtvssAAAYPYDVPDYGSHHHHHH **241 HE_L_2QvqllesggglvqAggslrlscaasgSIfsANamGwYrqapgkQReLvAVissggstNyadsvkgrftisrdnskTOW91 ntVylqmnslraedtavyycMYSGSYYYTPNDYwgqgtlvtvssAAAYPYDVPDYGSHHHHH H**242 Hu3TOevqllesggglvqpggslrlscaasERIFSTDVMGwYrqapgkQReLvAVVSARGTTNYLDAVKG W85_ArftisrdnskntlylqmnslraedtavyycYVRETTSPWRIYwgqgtlvtvssAAAYPYDVPDYGSHHHHHH** 243 Hu3TOevqllesggglvqpggslrlscaasERIFSTDVMGwYrqapgkgleLvAVVSARGTTNYLDAVKGrfW85_BtisrdnskntlylqmnslraedtavyycYVRETTSPWRIYwgqgtlvtvssAAAYPYDVPDYGSHHHHHH** 244 Hu3TOevqllesggglvqpggslrlscaasERIFSTDVMGwvrqapgkglewvsVVSARGTTNYLDAVKGrftW85_C isrdnskntlylqmnslraedtavyycYVRETTSPWRIYwgqgtlvtvssAAAYPYDVPDYGSHHHHHH** 245 Hu3TOQvqllesggglvqpggslrlscaasERIFSTDVMGwYrqapgkQReLvAVVSARGTTNYLDAVK W85_DGrftisrdnskntlylqmnslraedtavyycYVRETTSPWRIYwgqgtlvtvssAAAYPYDVPDYGSHHHHHH** 246 HE_LM_evqllesggglvqpggslrlscaasERIfsTDVmGwYrqapgkgReLvAVVsARgTtNyLdsvkgrftisrdn3TOW85skntlylqmnslraedtavyycYVRETTSPWRIywgqgtlvtvssAAAYPYDVPDYGSHHHHHH* * 247HE_L_3QvqllesggglvqEggslrlscaasERIfsTDVmGwYrqaAgkQReLvAVVsARgTtNyLdAvkgrftisTOW85 rdnskntlylqmnslraedtaSyycYVRETTSPWRIywgqgtlvtvssAAAYPYDVPDYGSHHHHHH** 248 HE_LM_evqllesggglvqpggslrlscaasERIfsTDVmGwYrqapgkgleLvAVVsARgTtNyLdsvkgrftisrdnsR45_L3TkntlylqmnslraedtavyycYVRETTSPWRIywgqgtlvtvssAAAYPYDVPDYGSHHHHHH** OW85249 Hu3TOevqllesggglvqpggslrlscaTsGTIFSGYTMGwYrqapgkQReLvAVISGGGDTNYADSVKG W69_ArftisrdnskDtMylqmnslraedtavyycYSREVTPPWKLYwgqgtlvtvssAAAYPYDVPDYGSHHHHHH** 250 Hu3TOevqllesggglvqpggslrlscaTsGTIFSGYTMGwYrqapgkgleLvAVISGGGDTNYADSVKGrfW69_B tisrdnskDtMylqmnslraedtavyycYSREVTPPWKLYwgqgtlvtvssAAAYPYDVPDYGSHHHHHH** 251 Hu3TOevqllesggglvqpggslrlscaasGTIFSGYTMGwvrqapgkglewvsVISGGGDTNYADSVKGrftiW69_C srdnskntlylqmnslraedtavyycYSREVTPPWKLYwgqgtlvtvssAAAYPYDVPDYGSHHHHHH** 252 Hu3TOQvqllesggglvqpggslrlscaTsGTIFSGYTMGwYrqapgkQReLvAVISGGGDTNYADSVK W69_DGrftisrdnskDtMylqmnslraedtavyycYSREVTPPWKLYwgqgtlvtvssAAAYPYDVPDYGSHHHHHH** 253 Hu3TOevqllesggglvqpggslrlscaTsGTIFSGYTMGwYrqapgkQReLvAVISGGGDTNYADSVKG W69_ErftisrdnskntMylqmnslraedtavyycYSREVTPPWKLYwgqgtlvtvssAAAYPYDVPDYGSHHHHHH** 254 HE_LM_evqllesggglvqpggslrlscaTsgTIfsGyTmGwYrqapgkgReLvAVisGggDtNyadsvkgrftisrdnsk3TOW69 ntMylqmnslraedtavyycYSREVTPPWKLywgqgtlvtvssAAAYPYDVPDYGSHHHHHH* *255 HE_L_3QvqllesggglvqTggslrlscaTsgTIfsGyTmGwYrqapgkQReLvAVisGggDtNyadsvkgrftisrdnTOW69 skDtMylqmnslraedtavyycYSREVTPPWKLywgqgtlvtvssAAAYPYDVPDYGSHHHHHH** 256 HE_LM_evqllesggglvqpggslrlscaTsgTIfsGyTmGwYrqapgkgleLvAVisGggDtNyadsvkgrftisrdnskR45L_3T ntMylqmnslraedtavyycYSREVTPPWKLywgqgtlvtvssAAAYPYDVPDYGSHHHHHH*OW69 * 257 ACP363 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSggggsggggsggggsDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 258 ACP364EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSggggsggggsggggsDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 259 ACP367EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSggggsggggsggggsDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 260 ACP369EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSggggsggggsggggsDIQMTQSPSSLSASVGDRVTITCKSSEKLWANVAWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 261 ACP370EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSggggsggggsggggsDIQMTQSPSSLSASVGDRVTITCKSSEKLWANVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 262 ACP380DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKrtvaapsvfifppsdeqlksgtasvvellnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstitlskadyekhkvyacevthqglsspvtksfnrgec 263 ACP381DIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKrtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec 264 ACP382DIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKrtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslssthlskadyekhkvyacevthqglsspvtksfnrgec 265 ACP435DIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKrtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgecggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss** 266 ACP436DIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKrtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgecggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss** 267 ACP437DIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKrtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslssthlskadyekhkvyacevthqglsspvtksfnrgecggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss** 268 ACP438DIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKrtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltskadyekhkvyacevthqglsspvtksfnrgecggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss** 269 ACP448DIQMTQSPSSLSASVGDRVTITCKSSEKLWANVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKrtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekhkvyaceythqglsspytksfnrgec** 270 ACP449DIQMTQSPSSLSASVGDRVTITCKSSEKLWANVAWYQQKPGKAPKLLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKrtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec** 271 ACP450DIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKLLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKrtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec** 272 ACP439aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlgcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKSSEKLWANVAWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK 273 ACP440aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKSSEKLWANVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK 274 ACP441aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKSSEKLWANVAWYQQKPGKAPKLLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK 275 ACP442aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKSSEKLWANVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK 276 ACP443aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKSSEKLWANVAWYQQKPGKAPKLLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK 277 ACP444aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKSSEKLWANVAWYQQKPGKcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK 278 ACP445aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKWYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK 279 ACP446aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKWYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK 280 ACP447aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKLLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK 281 ACP451aptssstkktqlqlehllldlqmilnginnyknpkltrmltfldympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpALFKSSFPpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 282 ACP452aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpALFKSSFPpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 283 ACP453aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpALFKSSFPpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 284 ACP454aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpALFKSSFPpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 285 ACP455aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpALFKSSFPpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 441 ACP456aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpALFKSSFPpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKcPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 286 ACP457aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpALFKSSFPpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkrvepksc**287 ACP458eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpALFK SSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkrvepksc** 288 ACP459eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 289 ACP460eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 290 ACP461eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 291 ACP462eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 292 ACP463eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 293 ACP464eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKcPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 294 ACP465vprdcgckpcictypevssvfifppkpkdvltitltpkvtcvvvdiskddpevqfswfvddvevhtaqtqpreeqfnstfrsvselpimhqdwlngkefkcrvnsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitdffpeditvewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagntftcsvlheglhnhhtekslshspgksggpALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 295 ACP466vprdcgckpcictypevssvfifppkpkdvltitltpkvtcvvvdiskddpevqfswfvddvevhtaqtqpreeqfnstfrsvselpimhqdwlngkefkcrvnsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitdffpeditvewqwngqpaenykntqpimdtdgsyfyysklnvqksnweagntftcsvlheglhnhhtekslshspgksggpALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 296 ACP467vprdcgckpcictypevssvfifppkpkdvltitltpkvtcvvvdiskddpevqfswfvddvevhtaqtqpreeqfnstfrsvselpimhqdwlngkefkcrvnsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitdffpeditvewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagntftcsvlheglhnhhtekslshspgksggpALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLW SAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 297 ACP468vprdcgckpcictvpevssvfifppkpkdvltitltpkvtcvvvdiskddpevqfswfvddvevhtaqtqpreeqfnstfrsvselpimhqdwlngkefkcrvnsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitdffpeditvewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagntftcsvlheglhnhhtekslshspgksggpALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLW SAVAWYQQKPGKcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 298 ACP469vprdcgckpcictvpevssvfifppkpkdvltitltpkvtcvvvdiskddpevqfswfvddvevhtaqtqpreeqfnstfrsvselpimhqdwlngkefkcrvnsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitdffpeditvewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagntftcsvlheglhnhhtekslshspgksggpALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 299 ACP470vprdcgckpcictvpevssvfifppkpkdvltitltpkvtcvvvdiskddpevqfswfvddvevhtaqtqpreeqfnstfrsvselpimhqdwlngkefkcrvnsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitdffpeditvewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagntftcsvlheglhnhhtekslshspgksggpALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKcPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 300 ACP471mdmrvpaqllgllllwlrgarcvprdcgckpcictvpevssvfifppkpkdvltitltpkvtcvvvdiskddpevqfswfvddvevhtaqtqpreeqfnstfrsyselpimhqdwlngkefkcrvnsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitdffpeditvewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagntftcsvlheglhnhhtekslshspgksggpALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkrvepksc**301 ACP382 DIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKrtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslssthlskadyekhkvyacevthqglsspvtksfnrgec** 302 ACP383eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 303 ACP384eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 304 ACP385eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLW SAVAWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 305 ACP386eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 306 ACP387eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 307 ACP388eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKcPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 308 ACP389eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcyvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss** 309ACP390aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 310 ACP391eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 311 ACP392aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 312 ACP393aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 313 ACP394aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 314 ACP395aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKcPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 315 ACP396aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss** 316 ACP397aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss** 317 ACP398aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkrvepksc** 318 ACP399EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIKsggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgstfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltGGssstkktqlqlehllldlqmilnginnyknpkltrmlsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 319 ACP400EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKsggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgstfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltGGssstkktqlqlehllldlqmilnginnyknpkltrmlsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 320 ACP401EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIKsggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgstfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltGGssstkktqlqlehllldlqmilnginnyknpkhrmlsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 321 ACP402EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKcPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKsggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgstfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltGGssstkktqlqlehllldlqmilnginnyknpkltrmlsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 322 ACP403evqllesggglvqpggslrlscaasgsifsanamgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvsssggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgstfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltGGssstkktqlqlehllldlqmilnginnyknpkltrmlsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 323 ACP404evqllesggglvqpggslrlscaasgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvsssggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgstfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltGGssstkktqlqlehllldlqmilnginnyknpkltrmlsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 324 ACP405EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkrvepkscsggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgstfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltGGssstkktqlqlehllldlqmilnginnyknpkltrmlsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 325 ACP406vprdcgckpcictvpevssvfifppkpkdvltitltpkvtcvvvdiskddpevqfswfvddvevhtaqtqpreeqfnstfrsvselpimhqdwlngkefkcrvnsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitdffpeditvewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagntftcsvlheglhnhhtekslshspgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkrvepksc** 326 ACP407vprdcgckpcictvpevssvfifppkpkdvltitltpkvtcvvvdiskddpevqfswfvddvevhtaqtqpreeqfnstfrsvselpimhqdwlngkefkcrvnsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitdffpeditvewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagntftcsvlheglhnhhtekslshspgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 327 ACP408vprdcgckpcictvpevssvfifppkpkdvltitltpkvtcvvvdiskddpevqfswfvddvevhtaqtqpreeqfnstfrsvselpimhqdwlngkefkcrvnsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitdffpeditvewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagntftcsvlheglhnhhtekslshspgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 328 ACP409vprdcgckpcictvpevssvfifppkpkdvltitltpkvtcvvvdiskddpevqfswfvddvevhtaqtqpreeqfnstfrsvselpimhqdwlngkefkcrvnsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitdffpeditvewqwngqpaenykntqpimdtdgsyfvysklnyqksnweagntftcsvlheglhnhhtekslshspgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 329 ACP410vprdcgckpcictvpevssvfifppkpkdvltitltpkvtcvvvdiskddpevqfswfvddvevhtaqtqpreeqfnstfrsvselpimhqdwlngkefkcrvnsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitdffpeditvewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagntftcsvlheglhnhhtekslshspgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 330 ACP411vprdcgckpcictvpevssvfifppkpkdvltitltpkvtcvvvdiskddpevqfswfvddvevhtaqtqpreeqfnstfrsvselpimhqdwlngkefkcrvnsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitdffpeditvewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagntftcsvlheglhnhhtekslshspgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKcPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 331 ACP412vprdcgckpcictvpevssvfifppkpkdvltitltpkvtcvvvdiskddpevqfswfvddvevhtaqtqpreeqfnstfrsvselpimhqdwlngkefkcrvnsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitdffpeditvewqwngqpaenykntqpimdtdgsyfvysklnyqksnweagntftcsvlheglhnhhtekslshspgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss** 332 ACP413elcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggsDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKrtvaapsyfifppsdeqlksgtasvvcllnnfypreakvqwkydnalqsgnsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec** 333 ACP414elcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatmttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesyckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggsDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKrtvaapsyfifppsdeqlksgtasvvcllnnfypreakvqwkydnalqsgnsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec** 334 ACP415aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIKggggsggggsggggsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 335 ACP416aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 336 ACP417aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIKggggsggggsggggsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 337 ACP418aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKcPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 338 ACP419aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvssggggsggggsggggsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 339 ACP420aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvssggggsggggsggggsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 340 ACP421EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIKggggsggggsggggsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistlt** 341 ACP422EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLW SAVAWYQQKPGKcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmlafympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistlt** 342 ACP423EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIKggggsggggsggggsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistlt** 343 ACP424EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKcPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmlafympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistlt** 344 Acp425EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvssggggsggggsggggsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistlt** 345 ACP426EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvssggggsggggsggggsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistlt** 346 ACP427aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIKggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss** 347ACP428aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss**348 ACP429aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIKggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss** 349ACP430aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKcPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss**350 ACP431aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIKggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss** 351ACP432aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss**352 ACP433aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIKggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss** 353ACP434aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKcPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss**265 ACP435 DIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKrtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgecggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss** 355 ACP371aptssstkktqlqlehllldlqmilnginnyknpkltrmltfldympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 356 ACP372aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 357 ACP373aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 358 ACP374aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 359 ACP375aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 360 ACP376aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKcPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 361 ACP377aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss** 362 ACP378aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkrvepksc* *363 ACP379eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkrvepksc** 364ACP368 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 365 ACP365EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKAREKLW SAVAWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 366 ACP366EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 367 ACP284EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS 368 ACP285EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsaSpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesSlatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppygeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS 369 ACP286EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsggggsrvipvsgparclsqsrnllkaddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS 370 ACP287EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGcGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKcLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS 371 ACP288EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqveysweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTcPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGcGTMVTVSS 372 ACP289aptssstkktqlqlehllldlqmilnginnyknpkltrmltfldympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpgpagmkglpgsevqlvesggglvqpgnslrlscaasgftfskfgmswvrqapgkglewvssisgsgrdtlyaesvkgrftisrdnakttlylqmnslrpedtavyyctiggslsvssqgtlvtvssggggsggggsggggsggggsggggsggggssggpgpagmkglpgsevqlvesggglvqpggslrlscaasgftfssytlawvrqapgkglewvaaidsssvtvspdtvrgrftisrdnaknslylqmnslraedtavyycardsnwdaldywgqgttvtvssggggsggggsggggsdiqmtqspsslsasvgdrvtitckasqnvgtnvgwyqqkpgkapkaliysasfrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyytypytfgggtkveikhhhhhh 373 ACP290aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpgpagmkglpgsevqlvesggglvqpgnslrlscaasgftfskfgmswvrqapgkglewvssisgsgrdtlyaesvkgrftisrdnakttlylqmnslrpedtavyyctiggslsvssqgtlvtvssggggsggggsggggsggggsggggsggggssggpgpagmkglpgQVQLQESGGGLVQTGGSLRLSCTTSGTIFSGYTMGWYRQAPGEQRELVAVISGGGDTNYADSVKGRFTISRDNTKDTMYLQMNSLKPEDTAVYYCYSREVTPPWKLYWGQGTQVTVSSAAAYP YDVPDYGSHHHHHH 374ACP291aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpgpagmkglpgsevqlvesggglvqpgnslrlscaasgftfskfgmswvrqapgkglewvssisgsgrdtlyaesvkgrftisrdnakttlylqmnslrpedtavyyctiggslsvssqgtlvtvssggggsggggsggggsggggsggggsggggssggpgpagmkglpgQVQLQESGGGLVQEGGSLRLSCAASERIFSTDVMGWYRQAAEKQRELVAVVSARGTTNYLDAVKGRFTISRDNARNTLTLQMNDLKPEDTASYYCYVRETTSPWRIYWGQGTQVTVSSAAAYP YDVPDYGSHHHHHH 375ACP292aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpgpagmkglpgsevqlvesggglvqpgnslrlscaasgftfskfgmswvrqapgkglewvssisgsgrdtlyaesvkgrftisrdnakttlylqmnslrpedtavyyctiggslsyssqgtlvtvssggggsggggsggggsggggsggggsggggssggpgpagmkglpgQVQLQESGGGLVQAGGSLRLSCAASGSIFSANAMGWYRQAPGKQRELVAVISSGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCMYSGSYYYTPNDYWGQGTQVTVSSAA AYPYDVPDYGSHHHHHH376 ACP296aptssstkktqlqlehllldlqmilnginnyknpkltrmltfldympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSSGGPGPAGMKGLPGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKEIREIRREI EPEA** 377 Acp297aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKLLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKV EIKHHHHHHEPEA**378 ACP298aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKGLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKV EIKHHHHHHEPEA**379 ACP299aptssstkktqlqlehllldlqmilnginnyknpkltrmltfidympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfSqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKV EIKHHHHHHEPEA**380 ACP300aptssstkktqlqlehllldlqmilnginnyknpkltrmltfidympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSdahksevahrfkdlgeenfkalvliafaqylqqcpfedhvklvnevtefaktcvadesaencdkslhtlfgdklctvatlretygemadccakqepernecflqhkddnpnlprlvrpevdvmctafhdneetflkkylyeiarrhpyfyapellffakrykaafteccqaadkaacllpkldelrdegkassakqrlkcaslqkfgerafkawavarlsqrfpkaefaevsklvtdltkvhtecchgdllecaddradlakyicenqdsissklkeccekpllekshciaevendempadlpslaadfveskdvcknyaeakdvflgmflyeyarrhpdysvvlllrlaktyettlekccaaadphecyakvfdefkplveepqnlikqncelfeqlgeykfqnallvrytkkvpqvstptlvevsrnlgkvgskcckhpeakrmpcaedylsvvlnqlcvlhektpvsdrvtkccteslvnrrpcfsalevdetyvpkefnaetftfhadictlsekerqikkqtalvelvkhkpkatkeqlkavmddfaafvekcckaddketcfaeegkklvaasqaalglggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHHEPEA** 381 ACP302aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALAggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH** 382 ACP303EAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALASGGPGPAGMKGLPGStfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltGGssstkktqlqlehllldlqmilnginnyknpkltrmlSGGPGPAGMKGLPGSEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALAHHHHHH** 383 ACP304aptssstkktqlqlehllldlqmilnginnyknpkltrmltfldympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpgaspegrpesetsclvtttdfqiqtemaatmetsiftteyqHHHHHH** 384 ACP305elcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsclvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH** 385 ACP306aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsclvtttdfqiqtemaatmetsiftteyqSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH** 386 ACP307EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGStfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltGGssstkktqlqlehllldlqmilnginnyknpkltrmlSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH** 387 ACP308EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGStfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltGGssstkktqlqlehllldlqmilnginnyknpkltrmlSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH** 388 ACP309aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKSLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKV EIKHHHHHH** 389ACP310aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGQAPRLLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKV EIKHHHHHH** 390ACP311aptssstkktqlqlehllldlqmilnginnyknpkltrmltfldympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSeskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgkggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHHH** 391 ACP312eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgkSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmlafympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH** 392 ACP313aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKSGGPGPAGMKGLPGSeskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykappvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgkHHHHHH**393 ACP314vprdcgckpcictvpevssvfifppkpkdvltitltpkvtcvvvdiskddpevqfswfvddvevhtaqtqpreeqfnstfrsvselpimhqdwlngkefkcrvnsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitdffpeditvewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagntftcsvlheglhnhhtekslshspgkSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfldympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH** 394 ACP336aptssstkktqlqlehllldlqmilnginnyknpkltrmltfidympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 395 ACP337aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 396 ACP338aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 397 ACP339aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 398 ACP340aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss* *399 ACP341aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsevqllesggglvqpggslrlscaaserifstdvmgwyrqapgkqrelvavvsargttnyldavkgrftisrdnskntlylqmnslraedtavyycyvrettspwriywgqgtlvtvss**400 ACP342elcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 401 ACP343elcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 402 ACP344elcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 403 ACP345elcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 404 ACP346elcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss** 405 ACP347elcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsevqllesggglyqpggslrlscaaserifstdvmgwyrqapgkqrelvavvsargttnyldavkgrftisrdnskntlylqmnslraedtavyycyvrettspwriywgqgtlvtvss** 406 ACP348eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 407 ACP349eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclykgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 408 ACP350eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 409 ACP351eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 410 ACP352eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss** 411ACP353eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsevqllesggglvqpggslrlscaaserifstdvmgwyrqapgkqrelvavvsargttnyldavkgrftisrdnskntlylqmnslraedtavyycyvrettspwriywgqgtlvtvss** 412ACP354eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTK VEIK** 413ACP355eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatmttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGG GTKVEIK** 414ACP356eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesyckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTK VEIK** 415ACP357eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclykgfypsdiavewesngqpennykttppyldsdgsfflysrltvdksrwqegnyfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGG TKVEIK** 416ACP358eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtlvtvss** 417 ACP359eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggpGPAGLYAQpgselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevlnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsevqllesggglyqpggslrlscaaserifstdvmgwyrqapgkqrelvavvsargttnyldavkgrftisrdnskntlylqmnslraedtavyycyvrettspwriywgqgtlvtvss** 418 ACP360EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSggggsggggsggggsDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH** 419 ACP361EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH** 420 ACP362EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH** 421 ACP200lveepknlvktncdlyeklgeygfqnailvrytqkapqvstptlveaarnlgrvgtkcctlpedqrlpcvedylsailnrvcllhektpvsehvtkccsgslverrpcfsaltvdetyvpkefkaetftfhsdictlpekekqikkqtalaelvkhkpkataeqlktvmddfaqfldtcckaadkdtcfstegpnlvtrckdalaSGGPGPAGMKGLPGScdlpqthnlrnkraltllvqmrrlsplsclkdrkdfgfpqekvdaqqikkapipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfhritvylrekkhspcawevvraevwralsssanvlgrlreekSGGPGPAGMKGLPGSlveepknlvktncdlyeklgeygfqnailvrytqkapqvstptlveaarnlgrvgtkcctlpedqrlpcvedylsailnrvcllhektpvsehytkccsgslverrpcfsaltvdetyvpkefkaetftfhsdictlpekekqikkqtalaelvkhkpkataeqlktvmddfaqfldtcckaadkdtcfstegpnlvtrckdalaHHHHHH** 422 ACP201eahkseiahryndlgeqhfkglvliafsqylqkcsydehaklvqevtdfaktcvadesaancdkslhtlfgdklcaipnlrenygeladcctkqepernecflqhkddnpslppferpeaeamctsfkenpttfmghylhevarrhpyfyapellyyaeqyneiltqccaeadkescltpkldgykekalvssyrqGGGGSGGGGSGGSlveepknlvktncdlyeklgeygfqnailvrytqkapqvstptlveaarnlgrvgtkcctlpedqrlpcvedylsailnrycllhektpvsehvtkccsgslverrpcfsaltvdetyypkefkaetftfhsdictlpekekqikkqtalaelvkhkpkataeqlktvmddfaqfldtcckaadkdtcfstegpnlvtrckdalaSGGPGPAGMKGLPGScdlpqthnlmkraltllvqmrrlsplsclkdrkdfgfpqekvdaqqikkapipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfhritvylrekkhspcawevvraevwralsssanvlgrlreekSGGPGPAGMKGLPGSeahkseiahryndlgeqhfkglvliafsqylqkcsydehaklvqevtdfaktcvadesaancdkslhtlfgdklcaipnlrenygeladcctkqepernecflqhkddnpslppferpeaeamctsfkenpttfmghylhevarrhpyfyapellyyaeqyneiltqccaeadkescltpkldgykekalvssyrqGGGGSGGGGSGGSlveepknlvktncdlyeklgeygfqnailvrytqkapqvstptlveaarnlgrvgtkcctlpedqrlpcvedylsailnrvcllhektpvsehvtkccsgslverrpcfsaltvdetyvpkefkaetftfhsdictlpekekqikkqtalaelvkhkpkataeqlktvmddfaqfldtcckaadkdtcfstegpnlytrckdalaHHHHHH** 423ACP202 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsgggSGGPGPAGMKGLPGSggggsgggscdlpqthnlrnkraltllvqmrrlsplsclkdrkdfgfpqekvdaqqikkapipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfhritvylrekkhspcawevvraevwralsssanvlgrlreekggggsgggSGGPGPAGMKGLPGSggggsgggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH** 424 ACP203EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgscdlpqthnlrnkraltllvqmrrlsplsclkdrkdfgfpqekvdaqqikkaqaipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfhritvylrekkhspcawevvraevwralsssanvlgrlreeksggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 425 ACP204EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSsggpALFKSSFPpgscdlpqthnlrnkraltllvqmrrlsplsclkdrkdfgfpqekvdaqqikkaqaipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfhritvylrekkhspcawevvraevwralsssanvlgrlreeksggpALFKSSFPpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 426 ACP205EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSsggpPLAQKLKSSpgscdlpqthnlrnkraltllvqmrrlsplsclkdrkdfgfpqekvdaqqikkaqaipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfhritvylrekkhspcawevvraevwralsssanvlgrlreeksggpPLAQKLKSSpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 427 ACP206EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgscdlpqthslgsrrtlmllaqmrrislfsclkdrhdfgfpqeefgnqfqkaetipvlhemiqqifnlfstkdssaawdetlldkfytelyqqlndleacviqgvgvtetplmkedsilavrkyfqritlylkekkyspcawevvraeimrsfslstnlqeslrskesggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 428 ACP207EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSsggpALFKSSFPpgscdlpqthslgsrrtlmllaqmrrislfsclkdrhdfgfpqeefgnqfqkaetipvlhemiqqifnlfstkdssaawdetlldkfytelyqqlndleacviqgvgvtetplmkedsilavrkyfqritlylkekkyspcawevvraeimrsfslstnlqeslrskesggpALFKSSFPpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 429 ACP208EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSsggpPLAQKLKSSpgscdlpqthslgsrrtlmllaqmrrislfsclkdrhdfgfpqeefgnqfqkaetipvlhemiqqifnlfstkdssaawdetlldkfytelyqqlndleacviqgvgvtetplmkedsilavrkyfqritlylkekkyspcawevvraeimrsfslstnlqeslrskesggpPLAQKLKSSpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 430 ACP211EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGScdlpqthnlrnkraltllvqmrrlsplsclkdrkdfgfpqekvdaqqikkapipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfhritvylrekkhspcawevvraevwralsssanvlgrlreekSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHEIREIREI 431 ACP213lveepknlvktncdlyeklgeygfqnailvrytqkapqvstptlveaarnlgrvgtkcctlpedqrlpcvedylsailnrvcllhektpvsehvtkccsgslverrpcfsaltvdetyvpkefkaetftfhsdictlpekekqikkqtalaelvkhkpkataeqlktvmddfaqfldtcckaadkdtcfstegpnlvtrckdalaSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSlveepknlvktncdlyeklgeygfqnailvrytqkapqvstptlveaarnlgrvgtkcctlpedqrlpcvedylsailnrvcllhektpvsehvtkccsgslverrpcfsaltvdetyvpkefkaetftfhsdictlpekekqikkqtalaelvkhkpkataeqlktvmddfaqfldtcckaadkdtcfstegpnlvtrckdalaSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSlveepknlvktncdlyeklgeygfqnailvrytqkapqvstptlveaarnlgrvgtkcctlpedqrlpcvedylsailnrvcllhektpvsehvtkccsgslverrpcfsaltvdetyvpkeflcaetftfhsdictlpekekqikkqtalaelvkhkpkataeqlktvmddfaqfldtcckaadkdtcfstegpnlvtrckdalaHHHHHH** 432 ACP214eahkseiahryndlgeqhfkglvliafsqylqkcsydehaklyqevtdfaktcvadesaancdkslhtlfgdklcaipnlrenygeladcctkqepernecflqhkddnpslppferpeaeamctsfkenpttfmghylhevarrhpyfyapellyyaeqyneiltqccaeadkescltpkldgykekalvssyrqGGGGSGGGGSGGSlveepknlvktncdlyeklgeygfqnailvrytqkapqvstptlveaarnlgrvgtkcctlpedqrlpcvedylsailnrvcllhektpysehvtkccsgslverrpcfsaltvdetyypkefkaetftfhsdictlpekekqikkqtalaelvkhkpkataeqlktvmddfaqfldtcckaadkdtcfstegpnlvtrckdalaSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSeahkseiahryndlgeqhfkglvliafsqylqkcsydehaklyqevtdfaktcvadesaancdkslhtlfgdklcaipnlrenygeladcctkqepernecflqhkddnpslppferpeaeamctsfkenpttfmghylhevarrhpyfyapellyyaeqyneiltqccaeadkescltpkldgvkekalvssvrqGGGGSGGGGSGGSlveepknlvktncdlyeklgeygfqnailvrytqkapqvstptlveaarnlgrvgtkcctlpedqrlpcvedylsailnrvcllhektpvsehvtkccsgslverrpcfsaltvdetyypkefkaetftfhsdictlpekekqikkqtalaelvkhkpkataeqlktvmddfaqfldtcckaadkdtcfstegpnlvtrckdalaSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfeylkdnqaisnnisvieshlittffsnskakkdafnsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSeahkseiahryndlgeqhfkglvliafsqylqkcsydehaklyqevtdfaktcvadesaancdkslhtlfgdklcaipnlrenygeladcctkqepernecflqhkddnpslppferpeaeamctsfkenpttfmghylhevarrhpyfyapellyyaeqyneiltqccaeadkescltpkldgvkekalvssvrqGGGGSGGGGSGGS1veepknlvktncdlyeklgeygfqnailvrytqkapqvstptlveaarnlgrvgtkcctlpedqrlpcvedylsailnrvcllhektpvsehvtkccsgslverrpcfsaltvdetyvpkefkaetftfhsdictlpekekqikkqtalaelvkhkpkataeqlktvmddfaqfldtcckaadkdtcfstegpnlvtrckdalaHHHHHH** 433 ACP215EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsgggSGGPGPAGMKGLPGSggggsgggshgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcggggsgggSGGPGPAGMKGLPGSggggsgggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsgggSGGPGPAGMKGLPGSggggsgggshgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcggggsgggSGGPGPAGMKGLPGSggggsgggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH** 434 ACP240EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaggggsggggsggggsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHRHHHH 435 ACP241EAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDT1VIPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALASGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH** 436 ACP242iwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSSGGPGPAGMKGLPGSEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALAHHHHHH** 437 ACP243vprdcgckpcictvpevssvfifppkpkdvltitltpkvtcvvvdiskddpevqfswfvddvevhtaqtqpreeqfnstfrsvselpimhqdwlngkefkcrvnsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitdffpeditvewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagntftcsvlheglhnhhtekslshspgkSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltitiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppygeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH** 438 ACP244iwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktlitiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppygeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSSGGPGPAGMKGLPGSvprdcgckpcictypevssvfifppkpkdvltitltpkvtcvvvdiskddpevqfswfvddvevhtaqtqpreeqfnstfrsvselpimhqdwlngkefkcrvnsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitdffpeditvewqwngqpaenykntqpimdtdgsyfyysklnvqksnweagnthcsylheglhnhhtekslshspgkHHHHHH** 439 ACP245EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLSGGPGPAGMKGLPGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTM VTVSSHHHHHH 440 ACP247EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmtlclgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQVQLQESGGGLVQAGGSLRLSCAASGRTFSSVYDMGWFRQAPGKDREFVARITESARNTRYADSVRGRFTISRDNAKNTVYLQMNNLELEDAAVYYCAADPQTVVVGTPDYWGQGTQVTVSSHHHHHH

INCORPORATION BY REFERENCE

The entire disclosures of all patent and non-patent publications citedherein are each incorporated by reference in their entireties for allpurposes.

Other Embodiments

The disclosure set forth above may encompass multiple distinctinventions with independent utility. Although each of these inventionshas been disclosed in its preferred form(s), the specific embodimentsthereof as disclosed and illustrated herein are not to be considered ina limiting sense, because numerous variations are possible. The subjectmatter of the inventions includes all novel and nonobvious combinationsand subcombinations of the various elements, features, functions, and/orproperties disclosed herein. The following claims particularly point outcertain combinations and subcombinations regarded as novel andnonobvious. Inventions embodied in other combinations andsubcombinations of features, functions, elements, and/or properties maybe claimed in this application, in applications claiming priority fromthis application, or in related applications. Such claims, whetherdirected to a different invention or to the same invention, and whetherbroader, narrower, equal, or different in scope in comparison to theoriginal claims, also are regarded as included within the subject matterof the inventions of the present disclosure.

1-72. (canceled)
 73. A fusion polypeptide having the Formula:[D]-[L1]-[A]-[L2]-[D], wherein A is a human interferon (IFN) polypeptideselected from a human interferon alpha (IFNa) polypeptide or a muteinthereof or a human interferon beta (IFNb) polypeptide or a muteinthereof; L1 and L2 are each independently a protease-cleavablepolypeptide linker; and D is an IFN blocking moiety,
 74. The fusionpolypeptide of claim 73, wherein the IFN polypeptide comprises an IFNapolypeptide, functional fragment, or mutein thereof,
 75. The fusionpolypeptide of claim 73, wherein the IFN polypeptide comprises an IFNbpolypeptide, functional fragment, or mutein thereof.
 76. The fusionpolypeptide of claim 73, wherein D is an IFN blocking moiety, which alsoextends in vivo half-life.
 77. The fusion polypeptide of claim 74,wherein when the IFNa polypeptide and the IFNa blocking moiety areoperably linked by the protease-cleavable polypeptide linker, the fusionpolypeptide has attenuated IFNa-receptor activating activity, andwherein when cleavage of both linkers occurs, in vivo half-life of theIFNa polypeptide is substantially similar to that of naturally occurringhuman IFNa.
 78. The fusion polypeptide of claim 75, wherein when theIFNb polypeptide and the IFNb blocking moiety are operably linked by theprotease-cleavable polypeptide linker, the fusion polypeptide hasattenuated IFNb-receptor activating activity, and wherein when cleavageof both linkers occurs, in vivo half-life of the IFNb polypeptide issubstantially similar to that of naturally occurring human IFNb.
 79. Thefusion polypeptide of claim 74, wherein the IFNa-receptor activatingactivity of the fusion polypeptide is at least about 10X less than theinterferon-receptor activating activity of the IFNa polypeptide that isproduced by cleavage of the protease cleavable linker.
 80. The fusionpolypeptide of claim 75, wherein the IFNb-receptor activating activityof the fusion polypeptide is at least about 10× less than theinterferon-receptor activating activity of the IFNb polypeptide that isproduced by cleavage of the protease cleavable linker.
 81. The fusionpolypeptide of claim 73, wherein D comprises a serum albumin bindingdomain, a serum albumin, transferrin, or immunoglobulin Fc, or afragment thereof.
 82. The fusion polypeptide of claim 73, furthercomprising a tumortargeting domain.
 83. A fusion polypeptide having theFormula: [D1]-[L]-[A]-[L2]-[D2], wherein A is a human IFN polypeptide,L1 and L2 are each independently a protease-cleavable polypeptidelinker; and either D1 is human serum albumin or a fragment thereof, andD2 is a human serum albumin binding domain or D2 is human serum albuminor a fragment thereof, and D1 is a human serum albumin binding domain.84. The fusion polypeptide of claim 83, wherein D comprises an IFNreceptor or fragment thereof.
 85. The fusion polypeptide of claim 73,further comprising a half-life extension domain.
 86. A method oftreating a human subject with or at risk of developing cancer or a viralinfection associated with cancer, comprising administering to thesubject in need thereof an effective amount of a fusion polypeptidehaving the Formula: [D]-[L1]-[A]-[L2]-[D], wherein A is a humaninterferon (IFN) polypeptide, L1 and L2 are each independently aprotease-cleavable polypeptide linker; and D is an IFN blocking moietywhich also extends in vivo half-life.
 87. The method of claim 86,further comprising administering to the subject and an anti-PD-L1,anti-CTLA4, or anti-PD-1 antibody.
 88. The method of claim 86, furthercomprising administering to the subject an IL-2 polypeptide and/or anIL-12 polypeptide.